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AMERICAN SOCIETY OF ECHOCARDIOGRAPHY REPORT

American Society of Echocardiography Recommendations for Use of Echocardiography in Clinical Trials A Report from the American Society of Echocardiography’s Guidelines and Standards Committee and The Task Force on Echocardiography in Clinical Trials Writing Committee: John S. Gottdiener, MD (Chair), James Bednarz, BS, RDCS, Richard Devereux, MD, Julius Gardin, MD, Allan Klein, MD, Warren J. Manning, MD, Annitta Morehead, BA, RDCS, Dalane Kitzman, MD, Jae Oh, MD, Miguel Quinones, MD, Nelson B. Schiller, MD, James H. Stein, MD, and Neil J. Weissman, MD

TABLE OF CONTENTS I. INTRODUCTION ......................................1088 II. TECHNIQUES IN CARDIOVASCULAR ULTRASOUND ......................................1088 Two-Dimensional Echocardiography .......1088 M-Mode Echocardiography.......................1089 Doppler Echocardiography and Color Flow Imaging .................................................1089 Stress Echocardiography ..........................1089 Transesophageal Echocardiography.........1089 Three-Dimensional Echocardiography .....1090 Contrast Echocardiography ......................1090 Digital Acquisition and Storage ................1090 III. ANATOMIC AND FUNCTIONAL

From the University of Maryland Hospital, Baltimore, Md (J.S.G.); University of Chicago Hospitals, Chicago, Ill (J.B.); Cornell University-Columbia Presbyterian Medical Center, New York, NY (R.D.); St. John Hospital and Medical Center, Detroit, Mich (J.G.); Cleveland Clinic, Cleveland, Ohio (A.K., A.M.); Beth Israel-Deaconess Medical Center, Boston, Mass (W.J.M.); Wake Forest University Health Sciences, Winston-Salem, NC (D.K.); Mayo Clinic, Rochester, Minn (J.O.); Baylor College of Medicine, Houston, Tex (M.Q.); University of California-San Francisco, San Francisco, Calif (N.B.S.); University of Wisconsin Medical School, Madison, Wis (J.H.S.); Washington Hospital Center, Washington, DC (N.J.W.). These recommendations are endorsed by the American College of Cardiology Foundation. Reprint of this document, beyond single use, is prohibited without the prior written authorization of the ASE. Address reprint requests to the American Society of Echocardiography, 1500 Sunday Dr, Suite 102, Raleigh, NC 27607. J Am Soc Echocardiogr 2004;17:1086-1119. 0894-7317/$30.00 Copyright 2004 by the American Society of Echocardiography. doi:10.1016/j.echo.2004.07.013

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QUANTITATION OF CARDIAC CHAMBERS............................................1090 LV Linear Dimension and Wall Thickness ..............................................1090 LV Volumes and EF ..................................1090 Prolate-Ellipse........................................1090 Area-Length and Truncated Ellipsoid ...1090 Method of Discs....................................1091 Method of Multiple Diameters .............1091 LV Mass.....................................................1091 Reproducibility .....................................1091 LV Systolic Function.................................1092 Ejection Fraction...................................1092 Reproducibility .....................................1092 Segmental LV Function.........................1092 Tissue Doppler Mitral Annular Systolic Velocity .............................................1092 Midwall Fractional Shortening/LV Systolic Stress Relationship ............................1092 Pitfalls in LV Quantitation and Strategies for Obtaining Quantifiable Images.............1092 Recommendations for Measurement of LV Volumes, EF, Segmental Wall Motion, and LV Mass ......................................1093 LV Volumes and EF...........................1093 Segmental LV Function .....................1093 LV Mass .............................................1093 Diastolic LV Function ...............................1093 Mitral Inflow Velocities ........................1093 Pulmonary Venous Flow.......................1093 Tissue Doppler Measurement of Mitral Annular Velocity ...............................1093 Color M-Mode Flow Propagation Velocity .............................................1094 Reproducibility .....................................1094 Recommendations for Assessment of Diastolic Function .............................1094


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Right Ventricular Mass, Function, and Pressure.................................................1095 Left Atrial Size, Volume, and Function ............................................1095 Reproducibility..................................1095 Recommendations for Measurement of LA Size ...........................................1095 IV. VALVULAR STRUCTURE AND FUNCTION............................................1095 Reproducibility .........................................1095 Recommendations for Assessment of Valvular Structure and Function.........................1095 V. RELATED TECHNIQUES IN CARDIOVASCULAR RESEARCH............1096 Intravascular and Intracoronary Ultrasound.............................................1096 Reproducibility .....................................1096 Recommendations for Performance of IVUS and ICUS ..................................1096 Flow-Mediated Brachial Arterial Dilation Assessment of Endothelial Function ....1097 Reproducibility .....................................1097 Recommendations for Assessment of FMD With Brachial Ultrasound..................1097 Carotid Artery Imaging in Cardiovascular Clinical Trials—Measurement of IntimaMedia Thickness ...................................1097 Reproducibility .....................................1099 Recommendations for Measurement of CIMT..................................................1099 VI. APPLICATIONS OF ECHOCARDIOGRAPHY IN CLINICAL TRIALS ............................1099 Epidemiological and Observational Studies...................................................1099 Hypertension ............................................1101 Evaluation of Treatment Effects on LV Mass...................................................1101 Effects of Treatment of Systolic and Diastolic LV Function .......................1101 Intercenter Differences in Acquisition Quality ...............................................1101 Recommendations for Echocardiography in Hypertension Clinical Trials .............1101 Heart Failure .............................................1102 Resynchronization/Biventricular Pacing Studies in Heart Failure.....................1103 What to Measure With Echocardiography in Heart Failure Trials .......................1104 Recommendations for Echocardiography in Heart Failure Studies.........................1104 Myocardial Infarction............................1105 Clinical Trials With TEE: Stroke, Atrial Fibrillation, and Guidance of Interventional Procedures ............................................1105 Clinical Trials in Atrial Fibrillation: TEEGuided Cardioversion .......................1105 LA Appendage Closure Devices ...........1105

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PFO Closure Devices ............................1105 Recommendations for TEE-Guided Clinical Trials..................................................1105 Prosthetic Valves ......................................1106 Evaluating Prosthetic Aortic and Pulmonic Valves ................................................1106 Evaluating Prosthetic Mitral and Tricuspid Valves ................................................1107 Recommendations for Echocardiography in Assessment of Prosthetic Valves.......1107 Echocardiographic Assessments of Cardiac Toxicity: Opportunity and Challenge ..1108 Recommendations ................................1108 Commercial vs Noncommercial Studies: Influence on Trial Design, Data Interpretation, and Publication ............1108 Recommendations for EchocardiographerInvestigator Participation in Clinical Trials..................................................1108 VII. HOW TO EVALUATE AND CONTROL ECHO VARIABILITY IN CLINICAL TRIALS: METHODS FOR QUALITY CONTROL..1108 Methods to Limit Measurement Variability ..............................................1108 Equipment.............................................1109 Site Training..........................................1109 Core Laboratory ....................................1110 Sonographer Training ...........................1110 VIII. SUMMARY AND RECOMMENDATIONS FOR USE OF CARDIOVASCULAR ULTRASOUND IN CLINICAL TRIALS ............................1110

LIST OF TABLES Table 1. Major Applications of Echocardiography in Clinical Trials Table 2. Echocardiographic Measures of Diastolic Function Table 3. Recommendations for Echocardiography in Clinical Trials of Hypertension Table 4. Summary of Selected Trials With Ultrasound Measurements of Carotid Intima-Media Thickness as a Surrogate for Atherosclerosis Table 5. Echocardiography in Epidemiological Studies Table 6. Selected Multicenter Treatment Trials in Hypertension With Echocardiography Table 7. Echocardiography in Clinical Trials of Congestive Heart Failure Table 8. Commonly Used Echocardiography Measures in Heart Failure Trials Table 9. Echocardiography in Clinical Trials of Stroke Table 10. Recommendations for Use of All Cardiac Ultrasound Techniques in Multicenter Clinical Trials


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Table 1 Major applications of echocardiography in clinical trials 1. Epidemiology and genetics Define cardiac structural and functional phenotype. Identify cardiac parameters of prognostic significance. 2. Hypertension Measure LV mass and assess systolic and diastolic cardiac function. Assess effects of treatment on cardiac structure and function. 3. Prosthetic valves Assess prosthetic valve hemodynamics; required by FDA. 4. Myocardial infarction and coronary artery disease Assess disease impact on LV remodeling and LV function. Use of stress echocardiography to determine ischemic vulnerability, viability, functional capacity. Assess effects of interventions on cardiac structure and function. 5. Heart failure Assess LV systolic and diastolic function, LV remodeling, comorbidity (eg, mitral regurgitation, pulmonary hypertension). Patient selection for device therapy. Assess treatment effects, including reverse remodeling. 6. Noncardiovascular trials Assess potential cardiac toxicity of treatment of disease, eg, cancer (radiation, chemotherapy), diabetes (glitazones). 7. Miscellaneous Diet-drug valvulopathy, echocardiographic contrast agents, TEE-guided cardioversion, atrial fibrillation, interventional device trials, cardiac surgery trials. FDA, Food and Drug Administration; LV, left ventricular; TEE, transesophageal echocardiography.

I. INTRODUCTION Echocardiography is one of the most commonly performed noninvasive diagnostic tests in patients with known or suspected cardiovascular diseases. Echocardiography provides comprehensive evaluation of the cardiovascular structure, function, and hemodynamics that characterize disease processes (readers are referred to published ACC/AHA/ASE guidelines1-10 for an overview on clinical aspects of echocardiography). Moreover, there are no known side effects associated with echocardiography, even with frequent and repeat testing. Its real-time nature, portability, and relatively low cost make echocardiography adaptable to most clinical or research situations. Hence, echocardiography has been used successfully to provide mechanistic insights on therapeutic outcomes, and in some cases to measure functional and structural changes that are considered to be of therapeutic importance (ie, “surrogate” end points). New advances in echocardiography bring increased opportunity and enormous potential to evaluate the cardiac effects of disease and its treatment repetitively and noninvasively in clinical trials (Table 1). Although many clinical studies have been performed to evaluate echocardiographic techniques per se, these are not the focus of this report. The purpose of this communication is to discuss the utility of echocardiography in enhancing the value of clinical trials by identifying potential mechanisms of clinical end points and determining surrogate end points and to offer recommendations regarding its use. In addition to physicians with expertise in

echocardiography, this document is intended for project officers and others working with government or industrial sponsors who may not be familiar with echocardiography but need an in-depth overview of the types of information that can be provided by echocardiography and related techniques in clinical research. As with other diagnostic techniques, the various sources of acquisition and measurement variability need to be considered in the application of cardiovascular ultrasound to clinical research. Data are presented in the following sections on reproducibility of echocardiography; however, diagnostic reproducibility and accuracy may vary according to the clinical or research context in which echocardiography is used. The importance of determining reproducibility for specific laboratories, readers, clinical trials, and potential changes over time is discussed later in this document.

II. TECHNIQUES IN CARDIOVASCULAR ULTRASOUND The cardiovascular ultrasound examination (“echocardiography”) offers several imaging and hemodynamic modalities. Two-dimensional Echocardiography Two-dimensional (2D) echocardiography is the backbone of echocardiography. By displaying anatomic structures in real-time tomographic images, comprehensive visualization of the components of the beating heart is achieved. The distance of ultra-


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sound echoes along the vertical axis represents the depth of echo-producing structures, with brightness indicating the intensity of the returning echo. The examiner is required to obtain multiple, precisely oriented anatomic “slices� by aiming an ultrasound probe at the heart (cross-sectional scanning). Information regarding cardiac chamber size, wall thickness, global and regional systolic function, and valvular and vascular structures is readily available. B-mode imaging refers to cross-sectional 2D images displayed without motion. Such images can provide excellent detail of static structures and are used in vascular imaging to show high-resolution detail of atherosclerotic plaque and vascular structure. M-mode Echocardiography M-mode or motion-mode images are a continuous 1-dimensional graphic display that can be derived by selecting any of the individual sector lines from which a 2D image is constructed. M-mode echocardiography is useful for quantitating single dimensions of walls and chambers, which can be used to estimate chamber volumes and left ventricular (LV) mass when those structures are geometrically uniform. M-mode echocardiography also has high temporal resolution, which makes it useful for timing valve motion. Doppler Echocardiography and Color Flow Imaging The Doppler technique uses reflections from moving red blood cells to characterize blood flow in the central and peripheral circulation. Doppler echocardiography complements M-mode and 2D echocardiography by providing functional information regarding intracardiac hemodynamics, including systolic and diastolic flow, blood velocities and volumes, severity of valvular lesions, location and severity of intracardiac shunts, and assessment of diastolic function. There are 4 types of Doppler: pulsed-wave, continuous-wave, color flow mapping, and tissue Doppler. Pulsed-wave Doppler is useful for localizing and timing flow that is moving within the physiological range of velocities. Continuous-wave Doppler, which lacks spatial resolution, is useful for accurately measuring the gradients that drive pathological flow jets. Color flow mapping, by measuring velocity along each sector line of the 2D image and displaying the information as color-coded pixels, provides a composite picture of flow over a larger area; it is most useful for screening the valves for regurgitation and stenosis, imaging systolic and diastolic flow, detecting the presence of intracardiac shunts, and detecting coronary flow. Tissue Doppler detects the amplitude and phases of the relatively slow motion of the LV myocardium (usually at the base of the heart). It is useful as a means of studying diastolic function. Strain rate imaging11-14 is a rela-

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tively new technique in echocardiography of potential utility for evaluation of systolic and diastolic LV function. This modality records myocardial tissue velocities to provide information about rates of local compression and expansion, and in contrast to endocardial excursion, it is free of tethering by adjacent myocardial segments. Stress Echocardiography7,15-17 A stress echocardiogram7 uses any combination of the above echocardiography modalities, before and during (or shortly after) a physical or pharmacological stress intervention. Most commonly, a treadmill or exercise bicycle is used for exercise echocardiography. Alternatively, in patients who are unable to exercise, stress testing can be performed with pharmacological agents that increase myocardial oxygen demand (eg, dobutamine, often given with atropine) or vasodilators that produce coronary steal. These tests may have utility primarily in the detection of myocardial ischemia and viability but may also be used to assess the efficacy of coronary revascularization or antianginal medication. Special interventions such as isometric handgrip, cold pressor (immersion of the hand in ice water), mental stress tasks, and cardiac pacing have also been used in some research applications. Hemodynamic changes with stress can be assessed by Doppler. Overall, the sensitivity and specificity of stress echocardiography for detection of coronary disease has been comparable to that of nuclear scintigraphy, and stress echocardiography has had excellent prognostic value for prediction of clinical outcome.16 Transesophageal Echocardiography Transesophageal echocardiography (TEE) uses a miniature ultrasound probe mounted at the end of an endoscope. A physician inserts the probe into the esophagus and performs the examination while a nurse monitors the patient and administers sedative medications. Two-dimensional, M-mode, and Doppler techniques are performed during a TEE examination. TEE has the advantages of generally superior image quality to 2D echocardiography and better imaging of selected structures such as the left atrial (LA) appendage, pulmonary veins, and mitral regurgitant jets in patients with prosthetic mitral valves. However, TEE may be of limited utility in clinical trials because of its semi-invasive nature and added requirements for equipment and personnel. Nonetheless, in the STICH (Surgical Treatments for Ischemic Heart Failure) trial,18 TEE is being used for assessment of mitral valve structure and regurgitation. TEE has been used successfully in clinical trials during surgery to evaluate and monitor cardiac function and in trials of atrial fibrillation treatment and closure of patent foramen ovale (PFO).


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Three-Dimensional Echocardiography Three-dimensional (3D) echocardiography provides displays of cardiac structures or flow and offers the display of any 2D imaging plane within the 3D data set.19 Three-dimensional echocardiography can be performed in 2 ways: real-time acquisition or sequential acquisition and reconstruction of multiple 2D planes into a 3D model with a locator device. Real-time 3D technology has recently been introduced clinically and is currently being refined. Disadvantages of the non–real-time technique include nonsimultaneous acquisition and significant postacquisition reconstruction time. In clinical trials, 3D echocardiography offers the potential of improved quantitation of cardiac volumes and LV mass, which leads to greater accuracy, sensitivity, and reduced sample size.

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III. ANATOMIC AND FUNCTIONAL QUANTITATION OF CARDIAC CHAMBERS LV Linear Dimensions and Wall Thickness These fundamental measurements are used for almost all clinical trials that incorporate echocardiography. Linear dimensions are obtainable from correctly aligned 2D and M-mode images. M-mode recordings provide better temporal resolution for accurate timing of motion of cardiac walls and valves, whereas 2D provides better spatial orientation. From LV chamber internal dimensions in diastole and systole, LV ejection fraction (EF) and fractional shortening can be readily determined, and the addition of wall thickness allows derivation of LV mass.

Contrast Echocardiography

LV Volumes and EF

Commercially available contrast agents can be administered via venous injection to enhance the diagnostic quality of the echocardiogram.20 Currently, contrast agents are only approved by the Food and Drug Administration (FDA) for LV opacification, although many clinical studies have evaluated their use to assess myocardial perfusion. Venous contrast injections are used to enhance LV endocardial borders and Doppler signals and to assess myocardial perfusion. The use of contrast may permit utilization of technically difficult studies and increase the yield of 2D echocardiography for assessment of global and segmental LV function. This advantage must be balanced against the expense, inconvenience, and need for an intravenous line.

The use of single dimensions to accurately reflect volumes and global LV function requires symmetrical geometry and contraction of the LV, respectively, to minimize error. LV volume is one of the best prognostic parameters in patients after myocardial infarction and is a prerequisite for calculation of EF (the difference between end-diastolic and endsystolic volumes divided by end-diastolic volume), as well as LV mass (see below). Because 2D echocardiography is a tomographic technique, the slices it creates must be converted mathematically to volumes by one or more of several methods based on geometric models of the LV. These methods have been validated21-23; the accuracy of the prolateellipse, area-length, and truncated ellipsoid methods is limited to normally shaped and sized ventricles, whereas the biplane method of discs is accurate in abnormally shaped ventricles. Three-dimensional echocardiography methods are less geometry-dependent than 2D and may supplant 2D methods in the future. Prolate-ellipse. The so-called cube formula is based on a model of the LV as a prolate ellipse of revolution where V ⫽ 4/3 ␲ L/2 ⫻ D1/2 ⫻ D2/2, where D1 and D2 are orthogonal minor axes; L is the long axis, which equals 2 ⫻ D; and D1 ⫽ D2. Hence, the volume approximates D3, which has been taken as the single linear dimension representing the short axis of the LV at the tips of the mitral valve. Area-length and truncated ellipsoid. The arealength formula (so-called bullet formula) for LV volumes (V ⫽ 5/6 AL, where A ⫽ LV short-axis area and L ⫽ LV long axis) assumes a bullet shape of the LV. The truncated ellipsoid formula assumes that the ventricle resembles a truncated ellipsoid. Both methods use the parasternal cross-sectional short-axis image at the level of the papillary muscles. Similar to volumes obtained from linear dimensions, these methods are also subject to error in the case of

Digital Acquisition and Storage Clinical echocardiography is quickly moving from analogue videotape to digital acquisition and storage, and it is anticipated that multicenter clinical trials will also move in a similar direction. Digital acquisition and storage has many advantages in clinical trials, including high image quality, reproduction of images without loss of information, and long-term storage and transportability. Another important advantage is the ability to link study sites to core laboratories via the Internet or secure servers, with virtually no concern about geographic distance. In addition to elimating the mailing costs of physical media and reducing missing data, this facilitates rapid qualification of studies, quality control, and rapid data turnover. With digital acquisition, it is necessary to ensure that representative beats are obtained. Media used to transport the images (eg, compact disc, DVD, or magneto-optical disc) must be standardized so both the acquisition sites and central laboratory can view the images and calibration information.


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distortions of LV geometry. In patients in whom only a low parasternal window can be obtained, the short-axis view will distort LV geometry, resulting in gross overestimation of LV volume by either of these formulas. In these patients, it is better to use the prolate-ellipse formula with linear dimensions taken from anatomically correctly oriented apical views or a parasternal long-axis view, with care taken to obtain the minor dimension perpendicular to the long axis, which will be angulated on the monitor screen. Correct alignment of short-axis images (for the 2D bullet formula) is characterized by a circular image just at the level of minimal motion of the mitral valve structures (indicating a level between mitral tips and chordae tendineae). Linear dimensions from 2Dtargeted M-mode echocardiography should be derived through the center of this circular image, whereas optimal 2D linear dimensions (for cavity and walls) are obtained perpendicular to the septum and posterior wall in the parasternal long-axis view that shows the largest LV cavity area. Method of discs (Simpson’s Rule). This method summates volumes of multiple cylinders of equal height along the LV. It is the most useful in obtaining LV cavity volumes in the presence of distorted LV geometry. However, a technical trade-off is incurred, because apical views (preferably paired biplane views) of the LV must be used. These views, which image the LV endocardium in lateral (poor, relative to axial) resolution, generally result in larger LV cavity volumes than the parasternal short-axis view required by the bullet formula, which images the LV endocardium mostly in axial (good) resolution. Moreover, it is sometimes difficult to identify the epicardial contour with certainty. Myocardial areas and derived volumes can be subject to substantial error. Hence, this method is not optimal for measurement of LV mass. Method of multiple diameters. LV EF and volumes can also be measured by the multiple diameter method,24,25 which uses the average of several diameters of the LV measured at end diastole and end systole from the parasternal long-axis and apical views. The diameter method is helpful in situations in which the apical views are suboptimal for adequate tracing of the endocardial contour or if the tomographic plane foreshortens the LV cavity. Its main advantage is incorporation of the parasternal long-axis view, which is available in the majority of patients. This method was applied by the SOLVD (Studies of Left Ventricular Dysfunction) investigators in an evaluation of LV remodeling.26 LV Mass The single largest application of echocardiography in epidemiology and in therapeutic trials has been the estimation of LV mass in free-living popula-

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tions27-33 and its change with antihypertensive therapy in clinical trials.34,35 All LV mass algorithms, whether based on M-mode, 2D, or 3D echocardiography, are based on subtraction of LV cavity volume from the volume enclosed by the LV epicardium to obtain an LV muscle “shell” volume. This shell volume is then converted to mass by multiplying by myocardial density (1.04 g/mL). To obtain the shell volume, the echocardiogram must be capable of imaging the interface between the LV blood pool and endocardium, as well as between the epicardium and pericardium. In principle, all the methods described above for LV volumes should be able to obtain LV volumes enclosed by the endocardium, as well as by the epicardium, thus allowing calculation of the shell volume and LV mass. However, in cases in which the shell volume is obtained by use of linear dimensions of LV cavity and septal wall thickness, cubing these linear dimensions can multiply even small errors. However, LV mass obtained with this method (LV mass ⫽ 0.8 ⫻ (1.04[(Dd ⫹ PW ⫹ VS)3 – (Dd)3] ⫹ 0.6g, where Dd ⫽ diastolic dimension, PW ⫽ posterior wall thickness, and VS ⫽ septal thickness) has been well validated by necropsy (r ⫽ 0.90, P ⬍ 0.001).37 Moreover, if care is taken to obtain accurate primary dimension measurements in an experienced core laboratory, good reproducibility of LV mass can be obtained.38 Linear dimensions can be obtained from either 2D-targeted M-mode images or directly from correctly aligned 2D images.38,39 Utilization of 2D linear dimensions overcomes the common problem of oblique parasternal images that result in overestimation of cavity and wall dimensions from M-mode echocardiography. LV mass can also be calculated from planimetered dimensions of 2D images obtained during real-time transthoracic imaging40 with the area-length or truncated-ellipsoid formulas as noted above. This specific methodology recommended by the American Society of Echocardiography (ASE) for 2D estimation of LV mass has also been validated.41 More recently, 3D echocardiography using a polyhedral surface reconstruction algorithm has been used to measure LV mass.42-44 This has the advantage of reducing dependence on geometric models and reducing error incurred from angulated images. Although this technique holds the promise of less variability and greater accuracy than 2D or 2Dtargeted M-mode echocardiography for estimation of LV mass45 and can measure change in LV mass with therapy in fairly small sample sizes,46 it has not yet been used in multicenter trials to measure LV mass and sequential change with therapy. Reproducibility. Reproducibility of echocardiography for measurement of LV volumes and LV mass may vary based on technique, laboratory, and patient population. In an early study of variability of repeated 2D echocardiography of normal subjects


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measured by multiple observers,47 the 95% confidence limits were wall thickness ⫾ 9%, LV diastolic volume ⫾ 11%, and LV mass ⫾ 12%. In a multicenter trial of hypertension treatment,48 reader agreement for LV mass between cardiologists was 0.83 but varied substantially by center. Another study evaluating an adolescent cohort in an observational study found greater interobserver variability (24 g) than intraobserver variability (19 g) for measurement of LV mass. In a multicenter study that used 2Dtargeted M-mode echocardiography, the test-retest reliability for measurement of change in LV mass not due to biological or methodological variability was found to be 59 g. However, when anatomically correct linear measurements directly from 2D were used in a more recent study49 with newer equipment, the test-retest reliability was 35 g (95% confidence limits), or approximately 18% of the baseline value. An 80% likelihood of true interval change would be predicted by a difference of 17 g on sequential studies. With 3D echocardiography, a 12% interobserver variability for LV mass has been reported,45 in contrast to that of 8% for magnetic resonance imaging (MRI) and 18% for 2D echocardiography, and correlation with MRI-measured LV mass was higher (r ⫽ 0.93, SEE ⫽ 9.2 g) than correlation of M-mode echocardiography with MRI (r ⫽ 0.73, SEE ⫽ 26 g). LV Systolic Function Ejection fraction. LV EF is a time-honored standard and a useful measurement in studies of heart failure, in epidemiology studies of coronary artery disease, and in monitoring the effects of drugs on the heart. Methods for echocardiographic measurement were discussed previously. Although visual (“eyeball”) estimation of EF is commonly used in clinical practice, it is not suitable in research studies, in which detection of small changes may be highly relevant. The expense and time requirements of 3D reconstruction methods have limited the application of these techniques in clinical trials, but real-time 3D acquisition and measurement may become the future method of choice for measuring LV EF in clinical trials. Reproducibility. Reproducibility of EF on echocardiography can be as good as about ⫾ 7%,50 and test-retest reliability is ⫾ 5%.51 Three-dimensional echocardiography has shown better accuracy (r ⫽ 0.94, comparison with MRI) than 2D echocardiography (r ⫽ 0.85).52 Segmental LV function. The visual semiquantitative evaluation (scoring) of segmental wall motion is based on qualitative assessment of endocardial excursion and the extent and timing of systolic thickening of myocardial segments. It has not yet been successfully supplanted by quantitative methods, although the application of Doppler methods of

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measurement of regional wall strain11,12,14,53 may allow this in the future. Strain rate imaging, in contrast to endocardial excursion, is free of tethering by adjacent myocardial segments and may have the potential to improve analysis of segmental LV function. Tissue Doppler mitral annular systolic velocity. Tissue Doppler techniques, which are simple to perform,54 record low-velocity Doppler information in the LV walls. Research55,56 has shown the value of systolic and diastolic measurements of mitral annular velocity using tissue Doppler techniques, which are beginning to be used in multicenter clinical trials. Midwall fractional shortening/LV systolic stress relationship. Contraction of muscle fibers in the LV

midwall may better reflect intrinsic contractility than does contraction of fibers at the endocardium, which is measured by EF or fractional shortening. It is possible to use mathematical models57,58 that compute midwall fractional shortening from linear measures of cavity size and diastolic and systolic wall thickness. Midwall fractional shortening has been found to be predictive of incident congestive heart failure.59 Although M-mode measures of LV function are problematic when there are marked regional differences in function, these more sophisticated measures may be useful in clinical trials such as in hypertension,60 in which symmetrical LV contraction is usually present because of case selection. Pitfalls in LV Quantitation and Strategies for Obtaining Quantifiable Images Foreshortening of the LV cavity by the operator is a common source of underestimation of LV end-diastolic and end-systolic volumes.61,62 EF, which is calculated as the difference between end-diastolic and end-systolic volume divided by end-diastolic volume, is less affected by LV foreshortening because the error is, in part, self-correcting. Intravenous contrast administration and harmonic imaging improve border detection and lessen foreshortening, with improved reproducibility and better correlation of volumes and EF with the standard of cardiac MRI.61-64 Images can be obtained at held expiration or during quiet respiration, but either approach should be applied consistently. If images are obtained during held expiration, care must be exercised to avoid a Valsalva maneuver, which can degrade image quality and alter cardiac volumes. If beats are selected during quiet respiration, at least 30 beats should be recorded, which should allow selection of at least 3 beats for averaging that display correct anatomic alignment. It is recommended that the LV be displayed in the most magnified presentation, ie, at the shallowest display depth that contains all components of the image that need to be assessed. Use of greater display depths than neces-


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sary results in the desired portions of the image being represented by fewer pixels. The resulting lower pictorial information content may increase measurement error. Additionally, frame rates may be slower at deeper display depths, potentially resulting in blurred endocardial definition and reduced temporal resolution. Recommendations for measurement of LV volumes, EF, segmental wall motion, and LV mass. Be-

cause all of these measurements except segmental wall motion are dependent on accurate and reproducible measurement of LV volumes, they share common recommendations for optimal methodology. LV volumes and EF. The ASE recommends that for most research purposes, EF should be measured from LV volumes rather than estimated by visual inspection,65 as is common in clinical practice. For volumes, we recommend the method of discs whenever good apical views can be obtained. If poorresolution apical images do not allow identification of endocardium or are foreshortened, the method of multiple diameters24 may be used. In individuals without major shape distortions or substantial dilation of the LV, it is acceptable to use linear dimensions that approximate the minor axis in systole and diastole to calculate volumes and EF. Two-dimensional estimation with the single-plane area-length formula is also acceptable. In the case of distorted LV geometry, biplane apical views should be used. In the case of suboptimal visualization of endocardium, even with tissue harmonic imaging, left heart contrast agents should be used to improve accuracy and reproducibility. Segmental LV function. The ASE recommends that the 17-segment model adopted by many professional societies in 2002, including the ASE,66 be used to assign the units of analysis of wall motion. Walls should be scored67 as 1 ⫽ normal, 2 ⫽ hypokinetic, 3 ⫽ akinetic, 4 ⫽ dyskinetic, and 5 ⫽ aneurysmal (diastolically deformed). The ASE also recommends that wall motion be judged by segmental thickening in addition to endocardial motion. LV mass. In adequately powered clinical trials evaluating participants without substantial dilation, major distortions of LV geometry, or both (eg, most therapeutic trials in hypertension), the ASE recommends that LV mass be measured with the model of a prolate ellipse of revolution, from linear dimensions of septal wall, LV cavity, and posterior wall along the LV minor axis, identified as the largest diameter perpendicular to the septum and posterior wall. These can be obtained by 2D-targeted M-mode or directly from correctly aligned 2D images. Although they are less desirable because of limitations of lateral resolution, apical windows may be used to obtain 2D linear dimensions perpendicular to the septum and lateral wall at the level of the mitral tips. An acceptable alternative is use of the area-length or

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truncated-ellipsoid formulas. Because of inherent difficulties in reliably identifying the boundaries of the LV free wall from base to apex in apical windows, the Simpson’s rule method is not currently recommended. Diastolic LV Function Measures of diastolic function are important in clinical trials of heart failure (particularly with preserved systolic function) and hypertension, as well as in epidemiological studies (Table 2). Research has demonstrated the prognostic value of diastolic function measured by echocardiography in several clinical contexts.59,68-77 At the present time, a multitude of Doppler-derived parameters have been used to evaluate diastolic function. The physiological basis of these measurements is beyond the scope of this document but is detailed in the accompanying references.78,79 Recommendations on how to record and measure these parameters have been made recently in a publication from the ASE.54 Information from mitral inflow, pulmonary vein flow, LV inflow propagation velocity, and mitral annular diastolic velocity can be used to determine 4 patterns of diastolic function that represent stages of relaxation and compliance abnormality. A recent classification proposed that diastolic dysfunction be graded in 4 stages that correlate with diastolic impairment and symptom class.80 Characterization of diastolic function patterns and estimation of LA pressure are possible in clinical trials. Mitral inflow velocities. Early peak filling velocity, which represents acceleration of blood across the mitral valve, and atrial peak velocity are traditional but still valid measures when applied carefully. Deceleration time, a measure of LV stiffness, can also be measured from mitral inflow recording of early filling and may be less influenced by loading conditions than some other measures. Pulmonary venous flow. Measurement of pulmonary venous flow was the first method to differentiate pseudonormal from normal LV filling, and it has been used to estimate mean LA pressure. However, consistent high-quality recordings in clinical trials using transthoracic echocardiography (TTE) may be difficult to obtain and time-consuming. Hence, pulmonary venous flow recording in clinical trials has largely been supplanted by tissue Doppler and color M-mode flow propagation. Tissue Doppler measurement of mitral annular velocity. Longitudinal velocities within the myocar-

dium can be recorded with pulsed-wave tissue Doppler from the apical window. Velocities at the basilar segments are obtained by placing the sample volume at the junction of the LV wall with the mitral annulus. Most commonly, recordings of septal and lateral anuli are obtained. Early diastolic velocity (Em, also referred to as Ea for annular velocity) has


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Table 2 Echocardiographic measures of diastolic function Measurement location and technique

Mitral inflow: pulsed-wave Doppler (continuous wave can be used for IVRT) Mitral inflow/color flow M-mode Mitral annulus/tissue Doppler

Measurements

Epk, Apk, E/A ratio, deceleration time, IVRT, A-wave duration Early/late diastolic fractional filling Velocity of LV inflow propagation (Vp) Peak velocity early filling (Ea) of septal or lateral annulus.

Pulmonary vein Doppler (pulsed wave)

Systolic/diastolic velocities, A-wave duration and depth.

LA area (4ch)/volume

Area/volume; fractional area/volume changes

Inferior vena cava size

Linear dimension (diameter)

Comments

All are preload dependent and may be operator dependent Less frequently used than previously Measurement may be subject to observer variability and LV cavity dimension Relatively preload independent. Linear measurement. Values dependent on location of sample volume. Combination of mitral inflow Doppler and tissue Doppler (Epk/Ea ratio) may be useful for estimation of LA mean pressure. May be technically problematic in largescale, multicenter trials. Useful in separating normal from pseudonormal patterns. Correlates well with Doppler diastolic function measures. Possibly reflects chronic effects of increased LA pressure. Related to right atrial mean pressure. Usually affected by respiration.

Apk, Peak velocity of A wave; Ea, mitral annular peak velocity of early filling, measured by tissue Doppler; Epk, peak velocity of E wave; IVRT, isovolumic relaxation time; LA, left atrium; pk, peak velocity; 4ch, four chamber view.

been shown to relate inversely to the time constant of early relaxation, tau. Like flow propagation velocity (Vp), Em has been shown to be fairly insensitive to preload when myocardial relaxation is impaired, and thus, it can be used to assess LV relaxation independently of the influence of LA pressure in individuals with diastolic dysfunction. At least one clinical trial of treatment of diastolic heart failure (iPRESERVE) is using measurements of mitral annular velocity and velocity of color flow propagation as Doppler surrogates for LA pressure. Em measurement is simple to perform, and because it yields a linear rather than a biphasic measure, it could supplant the E/A ratio as the most commonly used measure of diastolic function in the future. Color M-mode flow propagation velocity. Propagation velocity (Vp) is a measure of the rate of propagation of blood flowing from the mitral valve tips to the LV apex. It is derived from the early mitral inflow velocity by color M-mode echocardiography in the apical 4-chamber view and is inversely associated with tau measured with high-fidelity micromanometer-tipped catheters.81 Importantly, Vp has been shown to be fairly insensitive to changes in preload.82,83 Reproducibility. Intraobserver and interobserver correlations of peak mitral inflow velocities have been reported at âą–0.8984; however, test-retest reliability of mitral inflow velocities has been noted to be modest,51 with intraclass coefficients (rho) of correlations for early diastolic filling velocity (E), late filling velocity (A), and E/A ratio of 0.64, 0.65, and 0.12, respectively, possibly due to biological variability. Reproducibility of

inflow velocity is better when measured at the tips than at the mitral annulus. Test-retest reliability of Vp and lateral mitral annular velocities is excellent, with an intraclass coefficient of correlation (rho) of 0.90, although reliability for isovolumic relaxation time and deceleration time is less robust (rho 0.72 and 0.60, respectively). Recommendations for assessment of diastolic function. In hypertension trials, or trials of so-called

diastolic heart failure, in which ejection fraction is generally normal, we recommend using Em for the assessment of relaxation. If the available echocardiography machine is not capable of recording tissue annular velocities, Vp may be a useful alternative. However, in hypertrophic hearts with small LV cavities, Vp may provide falsely high values. Measurements derived from pulmonary vein velocity may not add significant information when the above parameters are available, and they are more difficult to obtain. For assessment of LA filling pressure, the ratio between early diastolic mitral inflow velocity and either mitral annular velocity (E/Em) or Vp (E/Vp) should be measured. Mitral annular velocity appears to be less subject to observer variability than color Mmode flow propagation. In clinical trials of participants with dilated cardiomyopathy and depressed LV EF (�40%), the mitral E/A ratio, isovolumic relaxation time, deceleration time, and measurements from pulmonary vein velocity are excellent indicators of filling pressures and are relatively simple to use. In the presence of atrial fibrillation, it will not be possible to measure atrial velocity of mitral inflow or


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Gottdiener et al 1095

the atrial contributions to pulmonary venous flow or annular velocity.

ear measurements or biplane LA areas may also be useful.96

Right Ventricular Mass, Function, and Pressure

IV. VALVULAR STRUCTURE AND FUNCTION

Right ventricular (RV) structure and function are affected importantly in systemic diseases that involve the LV, including hypertension, myocardial infarction, and congestive heart failure, as well as pulmonary vascular and parenchymal diseases. However, for technical and anatomic reasons, standardized and accepted measures of RV mass and EF by echocardiography have not been developed. RV systolic function has been evaluated visually or by area change determined from the apical 4-chamber view. Assessment of RV function may be enhanced in the future with the development of 3D echocardiography techniques. RV systolic pressure is a useful measure of pulmonary hypertension, and can be estimated from even small tricuspid regurgitant (TR) jets, which are commonly present, from the modified Bernoulli equation (4V2 ⫹ RAP), where V is peak velocity of the TR jet, and RA is estimated or assumed right atrial pressure. Left Atrial Size, Volume, and Function The left atrium enlarges in response to impaired LV filling and with mitral regurgitation and atrial fibrillation. LA size is therefore a useful adjunct in the assessment of diastolic function.85 LA size can be assessed by measuring a single dimension (eg, 2Dtargeted M-mode measurement of anteroposterior dimension). However, the LA enlarges in 3 planes, and a single dimension may fail to accurately represent LA volume.86 LA volume estimates from the planimetered LA area in the apical 4-chamber view correlate well with volumes obtained by biplane methods,87 previously validated by cine computerized tomography,88 and are superior to linear representations of LA size. Moreover, LA volume in a population-based study has been shown to reflect the presence and predict the incidence of cardiovascular disease.89 Nonetheless, even linear measurements of LA size have been of utility in clinical and epidemiological studies.85,90-94 LA passive and active emptying volumes can be obtained by measuring LV volume before atrial contraction, at LV end diastole, and at LV end systole.95 Reproducibility. Interobserver variability for Mmode, apical 4-chamber, and biplane estimations of LA volume has been reported to be 5 ⫾ 5, 6 ⫾ 6, and 8 ⫾ 9 mL, respectively.87 The test-retest reliability of 2D-targeted LA anteroposterior dimension is 5.5 mm, with an intraclass coefficient of correlation (rho) of 0.72.51 Recommendations for measurement of LA size. The ASE recommends planimetry of the LA

area from the apical 4-chamber view as a practical approach. Volume calculations from orthogonal lin-

Identification and qualitative assessment97 of valvular regurgitation are relatively simple with 2D echocardiography and color flow imaging. Such assessments are routinely used in clinical practice98 and are well described in standard texts99-101 and ASE guidelines.54 Measurement of color flow jet areas is operator and machine dependent, however, requiring careful attention to uniform image acquisition. Assessment of change in the magnitude of valvular regurgitation should utilize quantitative methods whenever possible. Volumetric assessments of regurgitation obtained by subtracting forward volume flow from total flow obtained from LV measurements sum the errors of chamber-volume estimations and are of limited utility. However, substantial experience has been obtained with the proximal isovelocity surface area (PISA) method with color flow Doppler for quantitation of mitral regurgitation.102-105 Effective regurgitation orifice area can be calculated as 6.28 ⫻ (R)2 ⫻ aliasing velocity/peak regurgitation velocity. Although they are quantitative, these techniques may be subject to acquisition and observer variability. Timing of velocity and PISA radius should be the same at mid systole to minimize variability. This technique is used primarily in mitral regurgitation and is more difficult to perform in other valvular regurgitant lesions. For studies that primarily assess valvular regurgitation as a covariate in evaluations of other echocardiographic end points, such as LV mass or systolic/ diastolic function, traditional qualitative methods are adequate. In general, clinical trials of valvular stenosis have been evaluations of prosthetic valves, discussed below. Reproducibility. Interobserver variability for measurement of PISA radius has been reported at 0.1 ⫾ 13.8%,106 and a 2.7-mm or greater change would have to occur to achieve 95% confidence of true change in severity of mitral regurgitation. Recommendations for assessment of valvular structure and function. The ASE recommends that

when qualitative assessment of valvular regurgitation, stenosis, and structure is performed, firm definitions should be established in advance as part of the study design. Quantitation of valvular thickness is limited by the technical characteristics of ultrasound and can be a problematic end point in clinical research. Leaflet mobility can be assessed qualitatively or by quantitative measurements of leaflet excursion. Quantitation of valvular regurgitation is desirable and recommended when feasible or in stud-


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Table 3 Recommendations for echocardiography in clinical trials of hypertension Principal investigator; director of core laboratory Participate in study design Select sites with capability and interest in research echocardiography Sonographer training Sonographer premeasurement LV mass measurement (ellipsoid model, linear LV cavity, wall thickness) Record systolic posterior wall thickness and LV dimension Biplane LV EF Diastolic function assessment Core laboratory reading

Quality assessment/improvement

Coordinate and participate in echo protocol, site selection, training, reading, analysis, manuscripts. Avoid partition values of LV mass for entry, or assess for regression to the mean. Sites submit sample echocardiogram for prequalification. Try to obtain sites capable of meeting recruitment goals and doing high-quality research echocardiography. Central meeting with participant demonstration; instructional videotape; Webcast. Sonographer measurements (not used for data) assist in critical assessment of echo quality before participant leaves the laboratory. Linear dimensions: targeted M-mode if eccentricity of parasternal short axis ⬍1.1, or 2D images with correctly aligned linear dimensions. Allows calculation of end-systolic stress. “Eyeball” EF as an alternative, but subject to challenge. LA area (apical 4 channel), question LA volumes (ellipsoid model), Epk, Apk, tissue Doppler annular velocity, other as practical. Fewer readers better than many (limits variability). Batch reading at end of study avoids temporal variability from drift in reading styles but limits ability to monitor study quality and is impractical in large, long-term studies. Alternative: periodic rereads of aliquot of test echocardiograms to measure reader drift. Question statistical correction of data as necessary. Acquisition: quality grades, communication, online recommendations for improvement as needed. Core laboratory; interobserver, intraobserver variability. Measure test-retest reliability and temporal drift in reading style.

Apk, peak mitral inflow velocity of atrial contraction measured by Doppler; EF, ejection fraction; LA, left atrium; LV, left ventricle.

ies primarily assessing valvular disease or heart failure. However, quantitation is subject to sources of variability in acquisition and interpretation similar to those with qualitative assessments. Therefore, the severity of valvular regurgitation should be determined by a combination of semiquantitative methods and more quantitative methods, such as PISA, depending on the objectives and size of the study. For recommendations regarding quantitation of valve areas, see below (“Prosthetic Valves”).

V. RELATED TECHNIQUES IN CARDIOVASCULAR RESEARCH Echocardiography research laboratories, and echocardiographers, have increasingly extended their activities from cardiac imaging to evaluation of anatomic and functional cardiovascular end points not usually evaluated in clinical echocardiography laboratories. Principally, these include assessment of endothelial function by measurement of flow-mediated brachial vasodilation (see below) and assessment of atherosclerotic burden by measurement of carotid artery intima-media thickness or identification of discrete carotid plaque. Additionally, cardiovascular ultrasound now involves partnerships with invasive cardiologists and radiologists in research applications of ultrasound imaging of coronary and peripheral arteries. Epidemiological studies and

studies of therapeutic interventions in hypertension and dyslipidemia that evaluate mechanistic end points require assessment of not just LV mass and function but also endothelial function and atherosclerosis. Hence, it is reasonable to incorporate these cardiovascular ultrasound assessments within the same site and core laboratories as traditionally used for echocardiographic research. Intravascular and Intracoronary Ultrasound (Table 32) Because intravascular ultrasound (IVUS) and intracoronary ultrasound (ICUS) are invasive techniques, their use in clinical trials will be essentially limited to participants with a clinical requirement for cardiac catheterization or as part of an interventional (stent) trial. Accordingly, ICUS and IVUS data are usually obtained by invasive cardiologists, not echocardiographers. Nevertheless, there are important diagnostic applications of ultrasound for assessment of artery and stent diameters, as well as presence and composition of atherosclerotic plaque and its change with therapy. Reproducibility. Interobserver differences in lumen, vessel, and plaque volume have been reported107 to be ⱕ0.4%, with coefficients of variation of ⱕ1.7% and test-retest differences of ⱕ2.6% (coefficients of variation ⱕ8.6%). Recommendations for performance of IVUS and ICUS. IVUS/ICUS should be limited to those labora-

tories that use the technology regularly (in general,


Journal of the American Society of Echocardiography Volume 17 Number 10

ⱖ5 times per week). In addition to the general recommendations presented later (VIII. Summary and Recommendations), equipment between sites should be standardized. The interpretation methods and nomenclature used in a clinical trial should be consistent with those set forth by the American College of Cardiology’s Task Force on Clinical Expert Consensus Documents.108 As with all other core laboratory analyses, intrareader and interreader variability should be assessed, and there should be documentation of the images analyzed and the measurements made. Flow-Mediated Brachial Arterial Dilation Assessment of Endothelial Function Endothelial dysfunction is a key step in atherogenesis that contributes to the initiation, propagation, and clinical manifestations of atherosclerosis. Abnormal endothelial function has been implicated both in early atherogenesis and in hypertension109,110 and has been demonstrated in humans before the appearance of intimal thickening by ICUS111 or other evidence of atherosclerosis.112 Lipid-lowering and other therapies have been shown to improve endothelial function.113-115 Hence, there is great potential for use of noninvasive measurement of endothelial function in clinical trials of hypertension and dyslipidemia, as well as in epidemiology studies.. Brachial artery ultrasound is a safe and noninvasive technique for detecting endothelial dysfunction and for following longitudinal changes in vascular reactivity in response to interventions. Normally, increased blood flow raises shear stress on endothelial cells, which leads to production of vasodilators and arterial dilation, which is mediated by nitric oxide produced by endothelial cells. This arterial dilation can be measured by 2D echocardiography. The diameter of the brachial artery is measured at baseline and in response to increased forearm blood flow, induced by occlusion of the arteries in the arm or forearm for approximately 5 minutes, the release of which leads to reactive hyperemia. The maximum change in brachial artery diameter from baseline in response to hyperemia, adjusted for the baseline diameter, defines flow-mediated dilation (FMD). Administration of nitroglycerin provides a control intervention to assess non– endothelium-dependent vasodilation. The techniques for assessing FMD have been reviewed in detail elsewhere.116 Although most reported studies have been singlecenter studies, multicenter studies have been reported and are under way, including the MultiEthnic Study of Atherosclerosis (MESA), the Cardiovascular Health Study (CHS), and the Framingham Heart Study. FMD frequently is used to assess the effect of interventions (eg, lipid lowering) on endothelial function. Crossover and parallel-group

Gottdiener et al 1097

trial designs have been used. Reproducibility. The interobserver variability (mean ⫾ standard deviation) is approximately 1.2 ⫾ 0.4% when the average FMD is 7 ⫾ 1%.117 In experienced laboratories with excellent reproducibility, a 2% to 3% improvement in FMD can be detected in crossover trials with about 15 to 30 subjects and in parallel-group trials with about 25 to 45 subjects per treatment arm.116,117 Recommendations for assessment of FMD with brachial ultrasound. Brachial artery ultrasound

studies of FMD should be performed in the morning in the fasting state, to eliminate circadian and postprandial variability in arterial diameters, and in a temperature-controlled room. Subjects who regularly use tobacco-containing products must refrain from such use for 12 hours. Because it is more comfortable and permits continuous arterial imaging, the ASE suggests the use of forearm occlusion in preference to upper-arm occlusion in multicenter clinical trial environments. These studies are technically challenging, and both technicians and readers have a steep learning curve. Because baseline brachial artery diameters typically are approximately 4 mm (less in children and women) and the observed change may only be 2% to 4%, changes in diameter of 0.12 to 0.16 mm must be detected. Therefore, the ASE suggests that experienced sonographers perform a minimum of 20 supervised scans and experienced readers review 5 to 10 high-quality scans by the specific study protocol before beginning unsupervised scanning. Ongoing scanning, at least 3 studies per month and 36 studies per year, should be performed, with at least semiannual review by an experienced reader to ensure maintenance of quality and adherence to the research protocol. Changes in FMD in response to interventions should be described in terms of absolute and percent change. Apparent changes in FMD oftentimes are attributable to changes in baseline brachial artery diameter, which may change with temperature, sympathetic tone, the postprandial state, and other physiological factors. Statistically, between-group comparisons should adjust for baseline artery diameters to minimize this effect. Carotid Artery Imaging in Cardiovascular Clinical Trials—Measurement of Intima-Media Thickness (Table 4) Carotid atherosclerosis has proved to be a useful surrogate for coronary atherosclerosis in epidemiological and prospective interventional trials of antiatherosclerotic agents. Ultrasonography permits noninvasive detection and quantification of abnormalities of carotid arterial structure, including wall thickening, plaque formation, and lumen enlargement. High-resolution B-mode ultrasound


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Table 4 Summary of selected trials with ultrasound measurement of carotid intima-media thickness as a surrogate for atherosclerosis Reference Number

Trial

Lipid-lowering trials CLAS 215

Treatment

Length, y

Subjects, n

Sites

Mean/Maximum

Colestipolniacin vs placebo Lovastatin vs placebo Atorvastatin vs pravastatin Probucol vs pravastatin vs diet

2

146

CCA

Mean (1)

Less progression with colestipol-niacin

3

919

Mean max (12)

1

161

2

246

CCA, bulb, ICA Far wall CCA CCA

CCA, bulb, ICA CCA, bulb, ICA CCA

Mean max (12)

Less progression with lovastatin More regression with atorvastatin Less progression with probucol or pravastatin than with diet Less progression with pravastatin Less progression with atorvastatin Less progression with pravastatin than placebo Less progression with metoprolol XL, less progression with fluvastatin than with placebo Less progression with pravastatin than placebo Less progression with pravastatin than placebo Less progression with pravastatin than placebo Less progression with lovastatin than placebo

124

ACAPS

216

ARBITER

217

FAST

218

PLAC-II

Pravastatin

3

151

219

ASAP

2

325

220

LIPID

Atorvastatin vs simvastatin Pravastatin

4

522

221

BCAPS

Metoprolol CR/XL and fluvastatin vs placebo

3

793

CCA, bulb, ICA

Mean (3)

222

KAPS

Pravastatin

3

447

CCA, bulb

Max (4)

223

REGRESS

Pravastatin

2

885

CCA, bulb, ICA

Mean (12)

224

CAIUS

Pravastatin

3

305

CCA, bulb, ICA

Mean max (12)

225

MARS

Lovastatin

4

188

CCA

Mean (2)

Lacidipine vs atenolol Metoprolol CR/XL and fluvastatin vs placebo

4

2334

CCA, bulb

Max (4)

3

793

CCA, bulb, ICA

Mean (3)

Antihypertension trials ELSA 125

Findings

Mean (2) Mean (6)

Mean (6) Mean (1)

221

BCAPS

226

PREVENT

Amlodipine

3

825

CCA, bulb, ICA

Mean max (12)

227

MIDAS

Isradipine vs hydrochlorothiazide

3

883

CCA, bulb, ICA

Mean max (12)

228

VHAS

Verapamil vs chlorthalidone

4

498

CCA, bulb, ICA

Mean max (6)

Less progression with lacidipine Less progression with metoprolol XL, less progression with fluvastatin than with placebo Less progression with amlodipine than placebo No difference in atherosclerosis progression, IMT difference favored isradipine No difference in atherosclerosis progression, verapamil greater after correcting for initial IMT


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Table 4 Continued Reference Number

Trial

Treatment

229

INSIGHT

230

SECURE

Nifedipine vs hydrochlorothiazide/ amilo-ride Ramipril vs vitamin E vs placebo

Length, y

Subjects, n

Sites

Mean/Maximum

Findings

4

439

CCA

Mean (1)

Less progression with nifedipine

4.5

732

CCA, bulb, ICA

Mean max (12)

Less progression with ramipril than placebo, no vitamin E effect

CCA, Common carotid artery; ICA, internal carotid artery; IMT, intima-media thickness; max, maximum.

permits accurate and reproducible identification and measurement of the combined thickness of the intimal and medial layers of the carotid artery. Several large epidemiological studies have shown significant associations between carotid intima-media thickness (CIMT) and both prevalent and incident coronary and cerebrovascular disease.118-121 Accordingly, measurement of CIMT has been a mainstay of cardiovascular epidemiological research for more than 2 decades. When scanning and reading are performed carefully, the reproducibility and reliability of CIMT measurement can be excellent.122,123 Cross-sectional analyses suggest that age-related increases in mean CIMT average approximately 0.010 mm per year for women and 0.014 mm per year for men in the internal carotid artery and 0.010 mm per year for both sexes in the common carotid artery.124 Similar values have been observed in prospective studies.215,225,226 Because the magnitude of clinically relevant differences in percentiles of CIMT and the progression rates are close to the resolution of vascular ultrasound transducers, highly standardized protocols are needed for performing and interpreting studies, which underscores the importance of high-quality, detailed image-acquisition protocols and highly skilled and trained ultrasonographers. Reproducibility. In highly trained centers, average reproducibility rates of 0.01 mm (standard error of the mean 0.01 mm) have been obtained on blinded repeat scans at 4-week intervals.122 With highly standardized protocols in populations with atherosclerosis, CIMT can be used as a continuous variable with sufficient reliability to detect annual changes in CIMT progression of approximately 0.01 mm relative to placebo, with a sample size between 100 and 200 subjects. Intrareader and interreader reliability have been reported at 0.915 and 0.872, respectively.123,125 Recommendations for measurement of CIMT. Scans should be obtained from multiple angles (circumferential scanning), and the near and far walls of multiple segments should be measured. For epidemiological and cross-sectional assessment, mean val-

ues of CIMT are sufficient. For longitudinal assessments, as in interventional trials, the use of mean maximal values from multiple sites provides the greatest sensitivity for detection of interval change. Measurements of carotid wall thickness can be made by manual tracing of wall interfaces or automated border-detection programs.126-128 It is important to monitor observer reproducibility throughout the study for each method of measurement; reproducibility differs between manual and automated techniques.

VI. APPLICATIONS OF ECHOCARDIOGRAPHY IN CLINICAL TRIALS The use of echocardiography in clinical trials was preceded by early investigations designed to define normative values for M-mode echocardiographic measurements of the LV, LA, aortic root dimension, and mitral valve.129-132 These initial studies were important in documenting the relationships of cardiac structural measurements to age and body size, as well as their accuracy and reproducibility. Epidemiological and Observational Studies The Framingham Heart Study was the first epidemiological study to use echocardiographic measurements, particularly of LV mass and geometry, to examine its cohort (1993-1998).34,133-137 Importantly, Framingham first demonstrated LV mass to be an independent predictor of cardiovascular events in a population-based sample. These and other normative and prognostic echocardiographic observations continue to be important as a basis for the current and future use of this technique in epidemiological studies and clinical trials (Table 5). Subsequently, other epidemiological studies, including the Cardiovascular Health Study, the Coronary Artery Risk Development in Young Adults (CARDIA) Study, the Olmstead County Heart Study, and the Helsinki Heart Study, have provided important cross-sectional and longitudinal information on relationships between cardiac structure and func-


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Table 5 Echocardiography in epidemiological studies No. of participants

No. of Echo sites

4950⫹

1

Per examination cycle

409

1

Up to 4 examinations over 10 years

Olmstead County (Mayo)233 Cardiovascular Health Study (CHS)234

2042

1

Twice

5888

4

Twice; 5-year interval

Elderly ⬎65 years; 14-year follow-up

1990, 1995

CARDIA235

1189

4

Twice; 5-year interval

1990, 1995

1100⫹

1

Multiple

Age 23-35 years; approximately 14-year followup Age 21-90⫹ years

577

1

Once

1989

LV mass calculable in 87% of subjects

Strong Heart Study237

3501

3

Once: 2nd Strong Heart Study exam

Random sample of Helsinki residents born 1904, 1909, or 1914 American Indian, CV events after exam

1993-1995

HyperGEN238

2966

4

Once: 1st HyperGEN exam

Cardiac disease and outcome in population with high rates of overweight and diabetes Heritability and genetic linkage of LV hypertrophy and dysfunction

3600⫹

3

Once: 4th Strong Heart Study exam/ Strong Heart Family Study (some Strong Heart Study participants reexamined)

Study 231

Framingham

Cornell-Worksite Studies232

Baltimore Longitudinal Aging Study129 Helsinki Aging Study236

Strong Heart Family Study239

Echo frequency

Population; follow-up

Year echo performed

Population-based CVD, original cohort and descendants; ⬎20 years Normotensive and hypertensive adults from employed population samples 3.5 years

1981-present

Assessment of LV mass, function, chamber size

1985-1998

Relations of LV structure and function to ambulatory blood pressure; longitudinal change

1997, 2002

Population-based assessment of systolic and diastolic dysfunction Population-based assessment of LV mass, systolic and diastolic function, chamber size. Comparison with wide array of clinical and biomedical variables. Population-based per above; comparison with wide array of clinical and biomedical variables Population-based aging study begun in 1940s

White & AfricanAmerican hypertensive adults from populationbased sources American Indians in large 3generation families, CV events after examination

1996-1999

2001-2003

Study aims

Heritability and genetic linkage of LV hypertrophy and dysfunction; LVarterial relations (with carotid ultrasound)


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Table 5 Continued No. of participants

No. of Echo sites

HyperGEN II

1000

4

Once: 2nd HyperGEN exam

Family Blood Pressure Program

6000

5

Once: 2nd Family Blood Pressure Program examination

Study

Echo frequency

Population; follow-up

Relatives of white and black hypertensive adults from population-based sources AfricanAmerican, Hispanic, and JapaneseAmerican adults from populationbased samples

Year echo performed

Study aims

2001-2003

Heritability and genetic linkage of LV hypertrophy and dysfunction

2001-2003

Heritability and genetic linkage of LV hypertrophy and dysfunction

CVD, Cardiovascular disease; CV, cardiovascular; LV, left ventricular.

tion, determined echocardiographically, with clinical expressions of disease and with clinical outcome. Importantly, in aging populations in which health becomes the outcome variable and disease status is the normative state, echocardiography may help define the phenotype of healthy aging. Epidemiological studies have additionally defined vascular phenotype and the presence and burden of atherosclerosis by measurement of carotid intima-medial thickening. Hypertension Evaluation of treatment effects on LV mass. Although the application of echocardiographic methods to trials of antihypertensive therapy has been shown to reduce LV mass and LV hypertrophy,138,139 some studies140-145 indicate that not all drugs are equally effective in reducing LV mass, even with comparable reduction of blood pressure. Table 3 summarizes the echocardiographic findings of several multicenter trials of antihypertensive treatment that used core laboratories and blinded readings. In appropriately designed studies, which are well powered and have sufficient duration of events ascertainment, important mechanistic information can be generated on relationships between clinical outcome and selection of therapy, based on its impact on cardiac function and structure. For example, in the LIFE (Losartan Intervention for Endpoint Reduction) study,146 not only was the experimental therapeutic limb associated with greater LV mass reduction, but LV mass reduction was also associated with improved clinical outcome independent of blood pressure lowering or treatment selection. Echocardiography has also been of use in demonstrating sustained reduction in LV mass in patients with hypertrophic obstructive cardiomyopathy after nonsurgical septal reduction therapy with intracoronary ethanol.147

Effects of treatment on systolic and diastolic LV function. Clinical studies that have evaluated ejec-

tion phase indices and diastolic filling with echocardiography148-158 have not demonstrated adverse effects of LV mass reduction on systolic or diastolic function during or after antihypertensive therapy. In fact, improvement may actually occur,159 particularly in diastolic performance, which may be an important therapeutic end point. Intercenter differences in acquisition quality. In previous large echocardiography trials, major differences in echocardiography quality have existed between field centers.160 For example, in one trial of antihypertensive monotherapy, the percent of readable echocardiograms for LV mass varied among centers from approximately 30% to 85%, probably owing to variation in technical performance. Importantly, extensive previous clinical experience in echocardiography was no guarantee of high-quality echocardiograms for quantitative research. Recommendations for echocardiography in hypertension clinical trials (Table 6). Sonographer

training is important to obtain reproducible images that are anatomically correctly oriented. Some of the flexibility in clinical examination techniques may be counterproductive to obtaining high-quality research studies. Specific training and monitoring of study quality as outlined in Section VIII is helpful. Given the large confidence intervals that may exist for measurement of LV mass, it could be argued that treatment trials should recruit participants with markedly increased LV mass. However, selection of participants with values for LV mass values substantially above (or below) the population mean can result in subsequent tests that reflect regression to the mean. Therefore, higher than “true� values for LV mass on an initial determination will tend to decrease on subsequent measurement. It is recommended that if possible, partition values


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Table 6 Selected multicenter treatment trials in hypertension with echocardiography Echo participants

Echo sites

587

15

240

902

Isradipine vs hydrochlorothiazide

145

LIFE (Losartan Intervention for Endpoint Reduction in Hypertension)

PRESERVE (Prospective Randomized Enalapril Study Evaluating Regression of Ventricular Enlargement) SANDS (Stop Atherosclerosis in Native Diabetics)

Study

References

Length, y

Study aims

Principal findings

Baseline, 1, 2 years

1

LV mass reduction in participants on competing singledrug assignments for mild-moderate hypertension

Diuretic effective for decreasing LV mass and LA size; diuretic, captopril, atenolol for LV mass

4

Baseline, annually for 4 years

4

LV mass reduction with monotherapy vs dietary-hygienic control

134

18

Baseline, 6 mo, 12 mo, 2 weeks after drug withdrawal

.5

241

754

47

Baseline, 1, 2, 3, 4, and 5 years

4.8

242

303

28

Baseline, 6 and 12 mo

1

*

488

4

Baseline, 18 and 36 mo

3

VA Cooperative Studies:

144

Monotherapy in Hypertension TOMHS (Treatment of Mild Hypertension Study)

94

Echo Frequency

All treatments associated with decrease in LV mass. Diuretic greater than other drugs at 1 year Isradipine vs Decreased LV mass hydrochlorothiazide and LA size with monotherapy for hydrochlorothiazide, LV mass and LA not with dimension isradipine. reduction Losartan vs atenolol Greater LV mass for LV mass reduction with reduction; losartan than with prognostic atenolol. Strong significance of LV predictive value of mass reduction lower ontreatment LV mass for outcome. Nifedipine vs No between-group enalapril for LV difference in LV mass reduction. mass reduction or Added medication mitral inflow as needed for filling velocities blood pressure control. Intensive treatment (LDL âą•75 mg/dl, BP âą•115/75 mmHg will reduce carotid IMT and LV mass more than standard treatment

In progress

BP, Blood pressure; IMT, intima-media thickness; LDL, low-density lipoprotein; LV, left ventricular. *Personal communication from Dr Richard Devereux.

for LV mass not be used as requirements for entry into the study. If such values are used, then batch reading at completion of the study (with continuous monitoring of studies for acquisition quality) should be done. This may not be practical in long-term studies. Additionally, over time, there may be changes in reading style that can systematically bias the interpretation of studies and lead to type I error. Periodic rereading of sample test echocardiograms will allow quantification of regression to the mean and of temporal reader drift.

Heart Failure (Table 7) Given the central role of alterations of cardiac function and structure in this important disorder, echocardiography is well-suited to the evaluation of patients with congestive heart failure in that it provides rapid assessment of systolic and diastolic LV (and RV) function, as well as comorbid valvular, myocardial, and pericardial abnormalities. Echocardiography is the most commonly used initial imaging test for patients with heart failure.161,162


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Gottdiener et al 1103

Table 7 Echocardiography in clinical trials of congestive heart failure Trial

Treatment

No. of Echo participants #

Prot.

SAVE243 SOLVD26

Captopril Enalapril

2231 2569

V-HeFT I & II244 V-HeFT III168

Vasodilators

1466

1466 M, S

Felodipine

450

260 M, S

CIBIS-II245 Hall et al246

Bisoprolol Metoprolol

2647 26

Most M, S 26 M, S

Doughty et al247 Tang et al248

Carvedilol

123

123 M, S

Carvedilol

256

256 M

Arcensio et al249 Ibopamine Capucci et al170 Pacing

18 38

512 M, S Y 301 M, S Y

18 M, S 38 M, S

MIRACLE169

Pacing

Jette et al250 Pu et al251 PRAISE-2252

Aerobic exercise Resistance exercise Amlodipine

39 96 1600

39 M, S 96 M, S 93 C, B

PEP-CHF167 CHARM253

Perindopril Candesartan

1000 6500

1000 M, S TBA TBA

I-PRESERVE, echo substudy*

Irbesartan

3600

500 M

453

Core lab

453 M

Echo role

O O

Echo variables

Echo findings

A, EF F, V, M

Echo predicts outcome ACE-inhibitor attenuates adverse LV remodeling Y O D, W Echo variables feasible in multicenter trial, predict mortality Y S, O D, V, EF, F, M, E Echo had good reproducibility, predicted mortality, hemodynamics Y S EF Y O V, EF, M Time course of EF improvement with beta-blocker treatments Y S, O V, EF Improvement in EF and LV remodeling in ischemic CHF Y O D, EF Baseline echo did not predict EF improvement Y S, O D, R Improvement in LV function Y S, O D, R Best atrioventricular interval with pacing for optimization of hemodynamics Y S, O D, EF, R Diastolic dimension, severity of mitral regurgitation, EF Y S, O D, EF No change with training Y S, O D, EF, R No change with training Y S, O D, EF, R EF and mitral regurgitation predicted mortality Y S, O D, EF, R Ongoing TBA TBA TBA Ongoing trial of diastolic and systolic heart failure Y S, O D, M, EF, F Ongoing trial of treatment of diastolic heart failure. Diastolic function measures include tissue Doppler

Treatment, Intervention; tested; Pts, participants; Echo#, number of participants in echocardiographic substudy (S, participant selection, O, outcome measurement); Prot., capture protocol (C, casual, M, mandated by protocol, B, baseline only, S, serial); Y, yes; N, no; A, LV areas; F, diastolic filling; V, LV volume; E, end systolic; M, LV mass; D, LV dimensions; W, wall thicknesses; R, regurgitation; ACE, angiotensin converting enzyme; CHF, congestive heart failure; LV, left ventricular; EF, ejection fraction. *Personal communication from Dr J. Gottdiener.

Despite the many multicenter trials involving large numbers of participants over the past 3 decades, until recently, cardiac imaging was used almost solely for participant selection and screening.163 Commonly, heart failure trials centered on participants with signs and symptoms of heart failure in the presence of decreased LV EF and LV dilation, and echocardiography or other imaging techniques, often abstracted from clinical records, were used primarily for entry criteria, to ensure a reduced LV EF and/or dilated chamber. This significant heterogeneity and lack of attempt at quality control of a pivotal entry criterion (EF) reduced costs but likely contributed to the variability of results. More recently, echocardiography has been used in a careful and systematic fashion in large, multicenter trials.164-167 The Veterans Cooperative Trials group (V-HeFT I, II, and III and Val-HeFT) pursued the development of echocardiographic methods for multicenter heart failure trials through a series of

substudies nested within large trials. V-HeFT-I and II were exploratory in nature.165 In V-HeFT-III, quantitative measurements were made at local sites, although quality control and oversight were provided by a central core laboratory.168 PEP-CHF, a pioneering trial in diastolic heart failure, declared Doppler echocardiographic outcomes to be particularly important.167 Mitral regurgitation has been shown to be an important prognostic factor in patients with heart failure, and several potential mechanisms for mitral regurgitation have been proposed. There are several clinical trials to attempt to improve participants’ heart failure status and their survival by reducing the amount of mitral regurgitation by a surgical or percutaneous device. In these trials, it will be important to use several semiquantitative and quantitative methods for evaluating the severity and mechanism of mitral regurgitation. Resynchronization/biventricular pacing studies in heart failure. Resynchronization of ventricular

contraction with biventricular pacing has been


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1104 Gottdiener et al

Table 8 Commonly used echocardiography measures in heart failure trials Most commonly used measures

LV EF and volumes (2D quantitative recommended)

Covariates of interest

A. Practical in large, multicenter trials: LV regional wall-motion abnormality, LV mass and wall thickness, qualitative or quantitative assessment of mitral regurgitation, carotid intima-media thickness, aortic distensibility/compliance, RV pressure, severity of tricuspid regurgitation.12 B. May be more practical in smaller studies: LV end-systolic stress, tissue strain rate imaging, LV midwall fractional shortening (“myocardial� function), aortic systolic velocity integral (estimate of stroke volume). C. Pertinent to biventricular pacing/resynchrony studies: LV electromechanical delay (time interval from onset of QRS to beginning of aortic flow recorded by pulsed- or continuous-wave Doppler), RV electromechanical delay (time interval from onset of QRS to beginning of pulmonary flow recorded by pulsed- or continuous-wave Doppler), interventricular conduction delay (difference between LV and RV electromechanical delay), septal to posterior wall-motion delay (shortest time interval from maximum excursion of ventricular septum and maximum excursion of posterior wall).

Diastolic function

A. Practical in large, multicenter trials: LA size (2D area/volume), Doppler E and A peak velocities, deceleration time, tissue Doppler mitral annular velocity. B. May be more practical in smaller studies: pulmonary vein velocities, color M-mode velocity of inflow propagation, isovolumic relaxation time; estimation of PA diastolic pressure from PR jet when present.

Echo to identify confounding nonmyocardial causes of heart failure

Screening for clinically significant aortic valve stenosis and regurgitation, evidence of constrictive pericarditis, pericardial effusion with tamponade, cardiac tumors, vegetations

A, Mitral inflow velocity of atrial contraction measured by Doppler; E, early diastolic mitral inflow velocity measured by Doppler; LA, left atrium; LV, left ventricle; PR, pulmonary regurgitation; PA, pulmonary artery; RV, right ventricle.

shown to improve symptoms of patients with dilated/ischemic cardiomyopathy and left bundle-branch block.169,170 With pacing, echocardiography studies have shown that the LV becomes smaller and systolic function improves after 3 to 6 months. However, not all patients with dilated cardiomyopathy and left bundle-branch block benefit from biventricular pacing. The degree of asynchrony between the right and left ventricles has been shown to correlate with the degree of reverse remodeling. The duration of QRS on an electrocardiogram does not predict the degree of ventricular dyssynchrony. However, echocardiographic parameters of ventricular dyssynchrony measured with M-mode, 2D, Doppler, and tissue Doppler identify participant populations that may benefit the most from resynchronization therapy and enable the monitoring of therapeutic response.169,171-173 Moreover, echocardiography can also determine surrogate end points of successful therapy, such as improvement in systolic function, mitral regurgitation, diastolic filling, and pulmonary hypertension. What to measure with echocardiography in heart failure trials. Heart failure is a clinical syndrome

that overlies complex alterations in cardiac structure and physiology and in peripheral vasculature and

neuroendocrine responses. Hence, there is no simple set of echocardiographic measures that is diagnostic of heart failure per se. However, in that echocardiography readily provides a rich array of information on virtually every cardiac abnormality (and some peripheral vascular abnormalities as well) that underlies heart failure, it is singularly well suited for heart failure trials. Table 8 is a list of echocardiographic measures, grouped by commonality and purpose of usage, that are reasonable for use in heart failure trials; it is not intended to be comprehensive. In trials of biventricular pacing, additional echocardiographic parameters to evaluate ventricular dyssynchrony are useful. Although the flexibility of echocardiography provides a great deal of information pertinent to heart failure, that very flexibility can lead to measurement variability. A recent report indicates that even with careful site selection, a specified protocol, and exclusion of participants with poor acoustic windows, the variability of basic outcome measures by echocardiography is greater than with alternative techniques such as radionuclide angiography and MRI,174 although echocardiography is considerably less expensive and more accessible. Moreover, harmonic imaging, contrast agents, and 3D echocardi-


Journal of the American Society of Echocardiography Volume 17 Number 10

ography all have the potential to improve the applicability and reproducibility of echocardiography. Use of contrast agents may have the largest potential for improving data yield and quality in clinical trials.63 Recommendations for echocardiography in heart failure studies. The successful application of echo-

cardiography in clinical heart failure trials depends on attention to quality control, including careful protocol design targeted to ensuring an adequate number of echocardiographic assessments without producing undue participant and sonographer burden; site training and monitoring; and echocardiographic coordination and interpretation by an experienced and competent core laboratory. Recommendations for assessment of echocardiography parameters used in heart failure trials are provided elsewhere in this document. Myocardial Infarction LV remodeling after acute myocardial infarction is a well-known pathological process that results in progressive dilatation (remodeling) and distortion of the LV. It is determined by the size, location, and extent of myocardial infarction, as well as the reperfusion status of the infarct-related artery. This process produces many echocardiographically recognizable changes, such as an increase in LV size and volume, mitral valve regurgitation, altered LV geometry, diastolic dysfunction, and other hemodynamic changes. It has been shown that LV volume is one of the most prognostic parameters after acute myocardial infarction. Optimal treatment of acute myocardial infarction minimizes the extent of LV remodeling and hence those echocardiographic changes associated with LV remodeling. Therefore, clinical trials to identify beneficial management modalities for participants with acute myocardial infarction should utilize the hemodynamic, structural, and functional changes related to LV remodeling as their end points. This requires accurate sequential assessment of LV size and volume, LV sphericity, and LV segmental function and quantitative assessment of mitral regurgitation, pulmonary artery pressure, and diastolic filling patterns. These assessments are discussed elsewhere in this document. Clinical Trials With TEE: Stroke, Atrial Fibrillation, and Guidance of Interventional Procedures Stroke is the third-leading cause of death in the United States,175 and approximately 15% of strokes are considered to have a cardioembolic source.176 The causes of cardioembolism include nonvalvular atrial fibrillation in 45% of patients, LV dysfunction in 25%, rheumatic heart disease in 10%, prosthetic valves in 10%, and other miscellaneous causes, such as endocarditis and cardiac

Gottdiener et al 1105

tumors, in 10%.177 Echocardiography has been important in clinical trials178,179 in identifying sources of cardioembolism.177 In suspected cerebral embolism, TTE is of use in identifying the presence of LV thrombus and cardiac comorbidity such as LV hypertrophy or LV dysfunction. However, the yield is low for identifying and characterizing potential sources of cardioembolism such as PFO, atrial septal aneurysm, thoracic aortic atheromas, and clot in the LA appendage. TEE is of greater utility than TTE in these circumstances,180-183 as well as for measurement of LA appendage velocity, itself a predictor of thrombus and stroke.184,185 There have been several stroke and atrial fibrillation trials in which echocardiography has played a major role (Table 9), including the SPAF III trial186 and the ACUTE multicenter trial.178 In SPAF III, TEE was useful in defining stroke risks of atrial fibrillation on the basis of LA abnormalities (LA appendage thrombus, dense spontaneous echocardiography contrast, or LA appendage flow �20 cm/s) and complex atheroma plaque.187 In the WARSS trial188 of participants with stroke, which compared the value of warfarin with that of aspirin for prevention of recurrent stroke, all participants had TEE at randomization. In a substudy, TEE was used to determine the relationship between PFO and recurrent stroke.183 With warfarin or aspirin therapy, the presence of PFO in those with stroke did not increase the chance of adverse events regardless of PFO size or the presence of atrial septal aneurysm. Clinical trials in atrial fibrillation: TEE-Guided Cardioversion. TEE with short-term anticoagulation

has been proposed as an alternative strategy in patients with atrial fibrillation who undergo electrical cardioversion. TEE involves greater logistic complexity than TTE. However, in the ACUTE study,189 TEE was shown to be feasible in a large multicenter study. With the use of uniform acquisition and interpretation criteria for identification of LA thrombus, it was found that the time to cardioversion and the composite rate of major and minor bleeding complications over an 8-week period were reduced with TEE-guided therapy. LA appendage closure devices. There are ongoing trials using TEE to assess the efficacy of percutaneous excluding devices of the LA appendage to decrease the risk of stroke.190 TEE and intracardiac echocardiography are also involved in the evaluation of pulmonary vein stenosis after radiofrequency ablation for atrial fibrillation.191,192 PFO closure devices. Recently, there has been increased interest in surgical and percutaneous catheter-based methods to close PFOs.193 With FDA approval of the Amplatzer and Cardioseal devices to close PFO, there is increasing interest in the use of TEE and intracardiac echocardiography194 to guide the closures.


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1106 Gottdiener et al

Table 9 Echocardiography in clinical trials of stroke Ref. no.

Trial

Treatment

No. of participants

186

SPAF III

Low-dose warfarin or ASA vs adjusted dose of warfarin in participants with stroke

382

178

ACUTE I

1227

254

ACUTE II

188

WARSS

183

PICSS

255

WARCEF

255

WATCH

TEE guided vs conventional therapy in participants undergoing DCC Low-molecular-weight heparin vs IV heparin in participants undergoing TEEguided cardioversion Warfarin or ASA in participants with stroke Warfarin or ASA in participants with PFO Warfarin or ASA in participants with low EF Warfarin, ASA, clopidogrel in participants with CHF and low EF

Outcome

Echo role

Findings

Stroke

TEE

Stroke, TIA, peripheral embolus

TEE

Stroke, bleeding, increased cost

TEE

Ongoing

2206

Recurrent embolic events or death

TTE

630

Recurrent stroke or death

TEE

2860

Recurrent stroke, death, or intracerebral bleed

TTE

No difference in recurrent stroke or death No difference between warfarin or ASA in participants with PFO Ongoing

4500

Stroke, death, or MI

TTE

Ongoing

200

High-risk group with LA abnormality and complex atheroma had stroke rate of 21% per year; adjusted dose of warfarin reduced rate of stroke No difference in stroke/ TIA; lowered bleeding in TEE arm

ASA, Aspirin; CHF, congestive heart failure; DCC, direct current cardioversion; EF, ejection fraction; IV, intravenous; MI, myocardial infarction; PFO, patent foramen ovale; TIA, transient ischemic attack; TEE, transesophageal echocardiography.

Recommendations for TEE-guided clinical trials. As with other multicenter trials, the ASE recommends use of standardized acquisition protocols and core laboratory measurement of TEE parameters. However, onsite qualitative and quantitative assessments, even though not used as study findings, can be useful tools to optimize the technical quality of studies. Inherently, both TTE and TEE may have significant variability in the detection of source of emboli in clinical trials. It is imperative that exact definitions of the sources of emboli be noted in the standard operating procedures manual, with illustrations (cine loops). Core laboratories should be used to verify the accuracy of the site data, ie, LA appendage thrombus, PFO, and atrial septal aneurysm. It is important to differentiate LA appendage thrombus from pectinate muscles, pulmonary vein limbus artifact, severe smoke, and sludge. In general, both TTE and TEE are useful in clinical trials involving cardioembolic stroke. The best yield is with TEE with the finding of LA appendage

thrombus, spontaneous echocardiography contrast, aortic atheroma, and PFO. Prosthetic Valves Manufacturers of prosthetic valves rely on Doppler echocardiographic measurements of valvular hemodynamics in vivo to fulfill FDA requirements195 for new device applications. Because most prosthetic valves are inherently stenotic, spectral Doppler can be used to evaluate valve performance in a manner analogous to native valve stenosis.54,196-202 The general principles for evaluating prosthetic valve function are similar to those of native valve stenosis. The velocity across the valve reflects the pressure gradient. Velocities and gradients through prosthetic valves depend on valve type and size, flow, and heart rate.198,200 Overall, Doppler pressure gradients correlate well with gradients by catheter.203 However, in certain valve prostheses, specifically smaller bileaflet valves, overestimation of gradients by


Journal of the American Society of Echocardiography Volume 17 Number 10

Doppler has been demonstrated and related to the “pressure-recovery” phenomenon.203,204 In newer stentless biological valves used for the aortic position, the valve orifice size is close to that of native valves, and consequently, Doppler velocities are near normal or, at most, slightly increased.205 However, stented biological and mechanical valves have smaller effective orifice areas than corresponding normal native valves, which results in higher velocities and therefore higher pressure gradients derived with the 4V2 equation. Evaluating prosthetic aortic and pulmonic valves. The following parameters are recom-

mended when evaluating an aortic prosthesis: peak transvalvular velocity (peakV), mean transvalvular gradient, peak LV outflow velocity, the ratio of peak LV outflow velocity to peakV (known as the Doppler velocity index or dimensionless index), and the effective orifice valve area, derived with the continuity equation. Details on the technical aspects of recording and measuring velocities from Doppler recordings are to be found in the “Recommendations for Quantification of Doppler Echocardiography” document from the ASE.54 Use of the continuity equation to measure prosthetic aortic valves requires calculation of the crosssectional area of LV outflow, commonly derived by use of the diameter of the LV outflow tract. When the diameter cannot be visualized reliably, the sewing ring diameter of the prosthesis can be used.200,203 Doppler-derived effective valve areas have been reported for few prostheses and appear to be related to valve size. In contrast, the Doppler velocity index is less dependent on valve size and is therefore quite useful when the valve size is not known at the time of the study.200,206 Prosthetic aortic valve regurgitation can be detected readily with transthoracic Doppler echocardiography. Color Doppler is quite sensitive, so that even the “built-in” functional regurgitation associated with some of the mechanical valves can be visualized.202,207 Whenever one finds more than trivial insufficiency by Doppler, it is recommended that the following parameters be used to assess severity: (1) the width of the regurgitant jet in the LV outflow tract relative to the LV outflow diameter, (2) the pressure half-time of the regurgitant jet recorded with continuous-wave Doppler, and (3) the magnitude and duration of the retrograde diastolic velocity in the upper descending aorta or the abdominal aorta, recorded with pulsed-wave Doppler. Pulmonic prosthetic valves are implanted infrequently, and thus fewer data are available on their evaluation. Because of the dynamics of RV ejection in native pulmonic stenosis, the peak instantaneous transvalvular gradient derived from the peak veloc-

Gottdiener et al 1107

ity is similar to the peak-to-peak gradient at catheterization. Evaluating prosthetic mitral and tricuspid valves. The following parameters are recom-

mended when evaluating a mitral prosthesis: (1) peak transvalvular velocity, (2) VTI of the transvalvular velocity, (3) mean transvalvular gradient, (3) pressure-half time (p 1/2t), and (4) effective mitral valve area (MVA). With valve obstruction, the peak velocity, VTI, mean gradient, and pressure half-time are generally increased, whereas mitral valve area is decreased (Table 2). Although the formula MVA ⫽ 220 ⫼ p 1/2t, validated in native mitral stenosis, has been applied to prosthetic mitral valves, it has never been properly validated.208 Nevertheless, most significantly obstructed mitral prostheses have a valve area derived by p 1/2t of 1.0 cm2 or less. However, as with native valves, the P 1/2t method can underestimate or overestimate mitral valve area in patients with significant aortic insufficiency, restrictive LV filling, severe relaxation abnormalities, arrhythmias, or sinus tachycardia. In these situations, the continuity equation may be applied using the LV outflow to determine stroke volume if there is no significant prosthetic valve regurgitation.209 No data are available for the application of the continuity equation in tricuspid valves. Detection and evaluation of prosthetic mitral valve regurgitation with TTE is hampered by ultrasound shadowing and Doppler flow masking that occurs when the sound waves are reflected by the prosthesis. This problem is more severe in mechanical valves than in bioprosthetic valves, which limits the sensitivity of transthoracic color and spectral Doppler for detection of prosthetic mitral valve regurgitation.210,211 Therefore, we recommend the use of a nonimaging continuouswave transducer in all participants with prosthetic mitral valves, because its lower frequency provides better penetration and can often record a regurgitant jet that has been missed by the imaging transducer. TEE is often needed to confirm this lesion and assess the severity of regurgitation. For the most part, prosthetic tricuspid valve regurgitation is easier to detect than prosthetic mitral regurgitation. Recommendations for echocardiography in the assessment of prosthetic valves. It is recognized

that the FDA guidelines for echocardiographic evaluation of prosthetic valves in clinical trials are an exhaustive compendium of Doppler measurements and flow data derived from 2D-estimated cardiac volumes. The potential for contradictory and confusing data is therefore large. Although comprehensive data acquisition is necessary to meet FDA guidelines, the echocardiography core laboratory principal investigator, in collaboration with the study sponsors, should specify which echocardio-


1108 Gottdiener et al

graphic measures are of primary interest (ie, most reliable) in contrast to those measures required for comprehensive evaluation but believed to be of lesser reliability. Because Doppler measurements may be heart rate dependent, heart rate at the time of recording should be reported. Measurements should be averaged over 3 to 5 cardiac cycles in sinus rhythm and 5 to 10 cycles in atrial fibrillation. When serial evaluations are made, particularly in clinical trials, it is recommended that the same instrument be used and the same sonographer perform the examination. A note should be made in the participant’s file as to the window that provided the best recording of the transvalvular velocity. Echocardiographic Assessments of Cardiac Toxicity: Opportunity and Challenge Echocardiography has been used extensively to assess potential cardiac toxicity from pharmacological agents. However, issues of potential cardiac toxicity may mandate rapid initiation and completion of clinical trials. This may make training, standardization, and quality assurance more difficult. Regardless of the difficult circumstances, it is the investigators’ responsibility to perform and interpret the echocardiographic studies using the same standards employed in other clinical trials. Recommendations. Whenever possible, a blinded control group should be used to determine whether the treatment group has developed cardiac toxicity. Arbitrary cutpoints should not be used to determine toxicity versus no toxicity because these cutpoints may introduce bias. For example, an EF less than a predetermined value should not be a cutpoint; rather, a statistically significantly lower EF in the treatment group than in the control group would indicate toxicity. A large study conducted in a short time may require substantial support, such as from a clinical research organization. Regardless of the support network for the study, the investigator responsible for the echocardiograms should write the echocardiography acquisition protocol and determine the interpretation methodology. The interpretation methodology must be determined before review of the echocardiograms. An analysis plan for the echocardiographic data pertinent to the hypotheses of the study should be developed with substantial input from the investigator responsible for the echocardiograms before the study begins. The investigator must have access to all of the echocardiographic data. The sponsor or a clinical research organization may support data analysis, but an investigator should be allowed to perform independent analysis to verify accuracy.

Journal of the American Society of Echocardiography October 2004

Commercial vs Noncommercial Studies: Influence on Trial Design, Data Interpretation, and Publication Echocardiographer-investigators should be integrally involved in the design of the echocardiographic examinations in clinical trials. This is important because echocardiographers, especially those who have had experience in the management of core laboratories, are aware of the quality-control issues involved in processing large number of studies, including appropriate training and monitoring of interreader and intrareader measurement variability, test-retest reliability, and temporal drift, as well as the practical requirements of ensuring smooth operation of the laboratory. Readers must also be blinded as to treatment group, demographics, and other key characteristics of participants whose echocardiograms they are interpreting. Important statistical issues include enrolling a sufficient number of subjects to ensure adequate power to test the hypotheses of greatest interest. In addition, the potential of regression to the mean is an important statistical consideration. Enrolling subjects with high (or low) partition values for a given parameter (eg, LV mass) may be attractive to the sponsor as a way to increase the likelihood of demonstrating a positive effect of a treatment. In the absence of a placebo control group, this can result in an erroneous interpretation treatment effect for all treatment arms because of regression to the mean, although with highly experienced core laboratories, this may not occur.38 Possible solutions to this problem include averaging measurements from multiple studies performed in close temporal proximity in the same subject and inclusion of a placebo group in the context of a randomized, controlled clinical trial. Patients give their consent to participate in clinical trials and provide consent with regard to the associated risks, discomforts, and demands on their time with the implicit understanding that the information obtained will be used to advance our understanding of disease and its treatment. Pharmaceutical or other industry sponsors of clinical trials have a responsibility to determine the safety and efficacy of their product and to present the information to the FDA in a timely and cost-effective way. These 2 goals of clinical trials may not always overlap completely, and it is the responsibility of the echocardiographer-investigator working with the industry sponsor to ensure that the clinical trial data are analyzed fully and completely and that the results of those analyses are presented for publication even if considered negative. Recommendations for echocardiographer-investigator participation in clinical trials. Ivestigators

must minimize actual or perceived conflicts of interest and disclose any financial support received from commercial sponsors. In commercially sponsored


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Gottdiener et al 1109

Table 10 Recommendations for use of all cardiac ultrasound techniques in multicenter clinical trials 1. Echocardiography principal investigator (PI) should be named. Level III ASE, experienced in clinical trials methodology and research applications of cardiovascular ultrasound 2. Use echocardiography central reading laboratory-under direction of echo PI a. Minimize number of readers b. Periodic joint reading sessions with echo PI to maintain parallel reading styles c. Monitor reader variability d. Rapid communication with study sites on study quality and opportunities for optimization e. Maintain communications with study sponsor on work throughput and quality issues 3. Standardized “hands-on� training of sonographers and readers onsite or at centralized meeting. When hands-on training not feasible, alternatives include instructional videotapes, Webcasts, etc. 4. Monitoring of sonographers for technical quality; encode study quality in database. 5. Record selective measurements and assessments by sonographer (or physician performing the echocardiogram) on transmittal sheet to encourage critical evaluation of echocardiogram before sending to core laboratory. 6. Appoint clinical site echo PI to oversee local acquisition quality 7. Late-model quality echocardiographic instrumentation, less than 5 years old a. Periodic calibration as needed with appropriate phantoms b. Digital recording and review when possible 8. Reading strategies a. Batch read when possible to minimize systematic temporal drifts. If studies are batch read at end of recruitment and after completion of intervention, continuous reading still needed for quality monitoring. Alternative to batch reading is periodic rereads of sample aliquot to measure trends in systematic temporal bias. Introduce corrective measures as needed. Other alternative is to reread initial studies at the same time as follow-up studies: b. Average multiple beats (minimum of 3 in regular rhythm, 5 in atrial fibrillation.) c. Single reader preferable. If duplicate independent reads of same studies, adjudicate differences with consensus reads. If multiple readers used for different studies, establish and adjust for interreader differences. Train for parallel reading styles in joint reading sessions. 9. Establish acquisition and reader variability a. Test-retest of small sample of participants, ie, same participant repeated over small interval, same machine, same sonographer, same reader. b. Blind duplicates for interreader and intrareader variability assessment. 10. Scientific participation of echocardiography PI and investigators in data analysis, presentations, publications.

studies, issues of particular importance include blinding of readers (for example, to demographics and treatment group), ensuring access of the investigators to all relevant echocardiographic and nonechocardiographic data, and maintaining editorial control of the preliminary and final publications.

VII. HOW TO EVALUATE AND CONTROL ECHO VARIABILITY IN CLINICAL TRIALS: METHODS FOR QUALITY CONTROL Methods to Limit Measurement Variability There are many ways to identify and control acquisition and measurement variability. Table 10 outlines approaches for decreasing variability that are generally applicable to measurement of LV mass and all other echocardiographic parameters. As part of all core laboratory practice, intrareader and interreader variability should be measured, with documentation of the images analyzed and measurements made. A potentially difficult problem is found in the changes in reading style that may occur over time and which may systematically bias the interpretation of studies and

lead to type I error. Periodic rereading of sample test echocardiograms will allow quantification of temporal reader drift and regression to the mean. Alternatively, batch reading of echoes at the completion of the study can be done, although this is likely to be logistically problematic, particularly in large clinical trials or epidemiological studies. A minimum number of readers should be used to limit the effects of interreader variability. Equipment. Contemporary (less than 5 years old) echocardiographic machines should be used in clinical trials. All machines should undergo regular maintenance by a qualified technician and have yearly evaluations of their internal electronic calibration. Internal calibration avoids the need to use ultrasound phantoms. Site training. Site training is a crucial step in ensuring high-quality, consistent study data. The physician lead investigator and the lead sonographer typically perform site training. Both the physician and sonographer selected to fulfill these responsibilities should have extensive research experience with image acquisition, measurements and calculations, and protocol training. In addition, they should have recently demonstrated a high level of personal expertise acquiring


1110 Gottdiener et al

and measuring the echocardiographic data described in the study protocol. The lead investigator of the study, with assistance from the lead sonographer, should coordinate the initiation training for all participating sites at a group training session. This meeting should include not only all investigators but also the participating sonographers and nurses, if possible. The suggested agenda for the initiation meeting should emphasize a review of the study goals and protocol, live demonstration of the image-acquisition protocol using a test subject, and presentation of the protocol measurements and calculations (even if these will be performed by the core laboratory). If possible, each site should acquire images from the same test participant to ensure consistent imaging techniques for all sites. If the individual sites are performing any of the measurements and calculations, these should be performed using the same images from the test participant. To minimize interoperator variability, specific guidelines should be included in the protocol regarding backup sonographer coverage and training/initiation requirements for the backup sonographers. The core laboratory should provide each site with an image-acquisition protocol, training or reference videotape, and a core laboratory contact list for questions or problems that may arise at the site. Additional responsibilities for the lead investigator and/or the lead sonographer include training replacement sonographers, if necessary, and providing follow-up information to the individual sites based on regular reviews of each site’s images and measurements. Training can be facilitated by specially prepared videotapes, CDs, internet Webcasts, or in-person investigator meetings. Careful and timely monitoring, especially at the start of the study, is important in allowing rapid feedback and correction of technical errors in image acquisition. For some studies, site submission of validation cases before the study begins will be useful to ensure compliance with the acquisition protocol and the ability to perform the aims of the echocardiography protocol properly. Core laboratory. Research has shown the value of core laboratories in multicenter clinical trials.212,213 A core laboratory is necessary to ensure standardization of data collection throughout the study and to provide centralized training and certification of all sonographers, who should have participated in a standardized training program. It is important to monitor changes in performance of personnel and equipment. To minimize reader variability, a practical minimum number of readers should be used, and interreader variability should be monitored. Training sets of echocardiograms should be interpreted jointly by all readers to encourage a parallel reading style, and interreader and intrareader variability should be assessed periodically. Measurement reading drift between readers must be identified and corrected as it occurs. The core reading

Journal of the American Society of Echocardiography October 2004

laboratory should encourage and assist in timely transmission of studies from study sites to the core laboratory and should notify study sites promptly of deficiencies in technical quality. The core laboratory must also cooperate fully with regulations regarding confidentiality of participant data and privacy and must be fully compliant with federal and industry standards for data integrity. The core laboratory should be involved in the study design. This is particularly important in estimations of sample size. The variability of echocardiography measurements can be mitigated by ensuring that a sufficiently large sample size is used to determine whether the treatment is associated with a change of a given magnitude in the echocardiography end point. If the study goals require determination of individual patient responses to therapy, then high test-retest reliability must be established. Sonographer training. A cardiac sonographer is an allied health professional who performs cardiac ultrasound examinations. The role of these individuals in clinical research is critical. The primary responsibility of the sonographer is to attain highquality, diagnostically correct ultrasound images and Doppler data. Echocardiography is operator dependent, requiring skill and experience in obtaining and integrating accurate diagnostic information. The educational requirements to reach this level of competence must incorporate detailed, structured, and comprehensive curricula.214 In clinical trials, particularly those in which multiple sites participate, sonographers should complete a standardized qualification process to ensure standardization of data acquisition.

VIII. SUMMARY AND RECOMMENDATIONS FOR USE OF CARDIOVASCULAR ULTRASOUND IN CLINICAL TRIALS Echocardiography has been and remains a valuable tool for evaluating the effects of disease and its treatment on cardiac anatomy and physiology. The value of echocardiography has been extended by related vascular ultrasound techniques, which can be performed with the same personnel and essentially the same instrumentation and which permit assessment of vascular atherosclerosis and endothelial function. Because of its near-universal availability, noninvasive nature, acceptance by participants, and relatively low cost, as well as the wealth of worldwide experience with echocardiography for more than 30 years, cardiac ultrasound is well suited for use in large clinical trials and epidemiological studies. However, the technical flexibility and large quantity of data obtainable with echocardiography can result in study variability and loss of focus in capturing the desired information. Optimal deploy-


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ment of cardiac ultrasound in clinical trials and epidemiological studies requires particular care beyond that used for patient care. Accordingly, the ASE has developed guidelines that we hope will assist in the design and implementation of protocols for clinical trials. These guidelines are based on the combined experience of the Committee, guided by an extensive literature on echocardiography in clinical investigations. Basic to these recommendations is the utilization of an ASE level 3 physician echocardiographer with experience in clinical trial methodology to guide protocol development, training of site sonographers, and interpretation of ultrasound data, preferably at a central reading (core) laboratory under the direction of the principal echocardiography investigator. Quality-control measures to assess and minimize acquisition and reading variability must be implemented as described above.

REFERENCES 1. Quinones MA, Douglas PS, Foster E, et al. ACC/AHA clinical competence statement on echocardiography: a report of the American College of Cardiology/American Heart Association/American College of Physicians-American Society of Internal Medicine Task Force on clinical competence. J Am Soc Echocardiogr 2003;16:379-402. 2. Cahalan MK, Stewart W, Pearlman A, et al. American Society of Echocardiography and Society of Cardiovascular Anesthesiologists task force guidelines for training in perioperative echocardiography. J Am Soc Echocardiogr 2002;15:647-52. 3. Gardin JM, Adams DB, Douglas PS, et al. Recommendations for a standardized report for adult transthoracic echocardiography: a report from the American Society of Echocardiography’s Nomenclature and Standards Committee and Task Force for a Standardized Echocardiography Report. J Am Soc Echocardiogr 2002;15:275-90. 4. Quinones MA, Otto CM, Stoddard M, Waggoner A, Zoghbi WA. Recommendations for quantification of Doppler echocardiography: a report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 2002;15:167-84. 5. Ehler D, Carney DK, Dempsey AL, et al. Guidelines for cardiac sonographer education: recommendations of the American Society of Echocardiography Sonographer Training and Education Committee. J Am Soc Echocardiogr 2001;14:77-84. 6. Shanewise JS, Cheung AT, Aronson S, et al. ASE/SCA guidelines for performing a comprehensive intraoperative multiplane transesophageal echocardiography examination: recommendations of the American Society of Echocardiography Council for Intraoperative Echocardiography and the Society of Cardiovascular Anesthesiologists Task Force for Certification in Perioperative Transesophageal Echocardiography. J Am Soc Echocardiogr 1999;12:884-900. 7. Armstrong WF, Pellikka PA, Ryan T, Crouse L, Zoghbi WA. Stress echocardiography: recommendations for performance and interpretation of stress echocardiography: Stress Echocardiography Task Force of the Nomenclature and Standards

Gottdiener et al 1111

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 1998;11:97-104. Cheitlin MD, Alpert JS, Armstrong WF, et al. ACC/AHA guidelines for the clinical application of echocardiography: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Clinical Application of Echocardiography): developed in collaboration with the American Society of Echocardiography. Circulation 1997;95:1686-744. American Society of Echocardiography. Recommendations for continuous quality improvement in echocardiography. J Am Soc Echocardiogr 1995;8:S1-28. Pearlman AS, Gardin JM, Martin RP, et al. Guidelines for physician training in transesophageal echocardiography: recommendations of the American Society of Echocardiography Committee for Physician Training in Echocardiography. J Am Soc Echocardiogr 1992;5:187-94. Edvardsen T, Gerber BL, Garot J, Bluemke DA, Lima JA, Smiseth OA. Quantitative assessment of intrinsic regional myocardial deformation by Doppler strain rate echocardiography in humans: validation against three-dimensional tagged magnetic resonance imaging. Circulation 2002;106: 50-6. Hoffmann R, Altiok E, Nowak B, et al. Strain rate measurement by Doppler echocardiography allows improved assessment of myocardial viability in patients with depressed left ventricular function. J Am Coll Cardiol 2002;39:443-9. Belohlavek M, Bartleson VB, Zobitz ME. Real-time strain rate imaging: validation of peak compression and expansion rates by a tissue-mimicking phantom. Echocardiography 2001;18:565-71. Abraham TP, Nishimura RA, Holmes DR, Belohlavek M, Seward JB. Strain rate imaging for assessment of regional myocardial function: results from a clinical model of septal ablation. Circulation 2002;105:1403-6. Voight JU, Exner B, Schmiedehausen K, Huchzermeyer C, Reulbach U. Nixdorff U, et al. Strain-rate imaging during dobutamine stress echocardiography provides objective evidence of inducible ischemia. Circulation 2003;107:2120-6. Gottdiener JS. Overview of stress echocardiography: uses, advantages, and limitations. Prog Cardiovasc Dis 2001;43: 315-34. Krivokapich J, Child JS, Walter DO, Garfinkel A. Prognostic value of dobutamine stress echocardiography in predicting cardiac events in patients with known or suspected coronary artery disease. J Am Coll Cardiol 1999; 33:708-16. Joyce D, Loebe M, Noon GP, et al. Revascularization and ventricular restoration in patients with ischemic heart failure: the STICH trial. Curr Opin Cardiol 2003;18:454-7. Rodevand O, Bjornerheim R, Aakhus S, Kjekshus J. Left ventricular volumes assessed by different new three-dimensional echocardiographic methods and ordinary biplane technique . Int J Card Imaging 1998;14:55-63. Mulvagh SL, De Maria AN, Feinstein SB, et al. Contrast echocardiography: current and future applications. J Am Soc Echocardiogr 2000;13:331-42. Feigenbaum H, Popp RL, Wolfe SB, et al. Ultrasound measurements of the left ventricle: a correlative study with angiocardiography. Arch Intern Med 1972;129:461-7. Folland ED, Parisi AF, Moynihan PF, Jones DR, Feldman CL, Tow DE. Assessment of left ventricular ejection fraction and volumes by real-time, two-dimensional echocardiography: a comparison of cineangiographic and radionuclide techniques. Circulation 1979;60:760-6.


1112 Gottdiener et al

23. Erbel R, Krebs W, Henn G, et al. Comparison of single-plane and biplane volume determination by two-dimensional echocardiography, 1: asymmetric model hearts. Eur Heart J 1982;3:469-80. 24. Quinones MA, Waggoner AD, Reduto LA, et al. A new, simplified and accurate method for determining ejection fraction with two-dimensional echocardiography. Circulation 1981;64:744-53. 25. Tortoledo FA, Quinones MA, Fernandez GC, Waggoner AD, Winters WL. Quantification of left ventricular volumes by two-dimensional echocardiography: a simplified and accurate approach. Circulation 1983;67:579-84. 26. Greenberg B, Quinones MA, Koilpillai C, et al. Effects of long-term enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction: results of the SOLVD echocardiography substudy. Circulation 1995;91: 2573-81. 27. Devereux RB, Pickering TG, Harshfield GA. Left ventricular hypertrophy in patients with hypertension: importance of blood pressure response to regularly recurring stress. Circulation 1983;68:470-6. 28. Byrd BF, Wahr D, Wang YS, Bouchard A, Schiller NB. Left ventricular mass and volume/mass ratio determined by twodimensional echocardiography in normal adults. J Am Coll Cardiol 1985;6:1021-5. 29. Liebson PR, Devereux RB, Horan MJ. Hypertension research: echocardiography in the measurement of left ventricular wall mass. Hypertension 1987;9(part 2):II-2-5. 30. Gardin JM, Savage DD, Ware JH, Henry WL. Effect of age, sex and body surface area on echocardiographic left ventricular wall mass in normal subjects. Hypertension 1987;9:II36-9. 31. Schiller NB. Considerations in the standardization of measurement of left ventricular myocardial mass by two-dimensional echocardiography. Hypertension 1987;9(suppl II):II33-5. 32. Savage DD, Levy D, Dannenberg AL, Garrison RJ, Castelli WP. Association of echocardiographic left ventricular mass with body size, blood pressure and physical activity (the Framingham Study). Am J Cardiol 1990;65:371-6. 33. Liebson P. Echocardiographic assessment of the left ventricle in hypertension: perspectives on epidemiologic studies and clinical trials. J Vasc Biol Med 1993;4:285-310. 34. Gottdiener, JG, Diamond, JA, Phillips RA. Hypertension: Impact of echocardiographic data on the mechanism of hypertension treatment options, prognosis, and assessment of therapy. In Otto, CM edit. The Practice of Clinical Echo Cardiography, Special Edition. Phildadelphia: WB Saunders; 2002. p 705-38. 35. Savage DD, Garrison RJ, Kannel WB, Levy D, Anderson KM, Stokes J III, Feinleib M, Castelli WP. The spectrum of left ventricular hypertrophy in a general population: The Framingham Study. Circulation 1987; 75:126-33. 36. Gardin JM, Arnold A, Gottdiener JS, et al. Left ventricular mass in the elderly: the Cardiovascular Health Study. Hypertension 1997;29:1095-103. 37. Devereux RB, Alonso DR, Lutas EM, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986;57:450-8. 38. Palmieri V, Dahlof B, DeQuattro V, et al. Reliability of echocardiographic assessment of left ventricular structure and function: the PRESERVE study: Prospective Randomized Study Evaluating Regression of Ventricular Enlargement. J Am Coll Cardiol 1999;34:1625-32.

Journal of the American Society of Echocardiography October 2004

39. Devereux RB, Roman MJ, Paranicas M, et al. Impact of diabetes on cardiac structure and function: the Strong Heart Study. Circulation 2000;101:2271-6. 40. Schiller NB, Shah PM, Crawford M, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography: American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 1989;2:358-67. 41. Park SH, Shub C, Nobrega TP, Bailey KR, Seward JB. Two-dimensional echocardiographic calculation of left ventricular mass as recommended by the American Society of Echocardiography: correlation with autopsy and M-mode echocardiography. J Am Soc Echocardiogr 1996;9:119-28. 42. King DL, Gopal AS, Keller AM, Sapin PM, Schroder KM. Three-dimensional echocardiography: advances for measurement of ventricular volume and mass. Hypertension 1994; 23:I-172-9. 43. Geil S, Rao L, Menzel T, et al. Determination of left ventricular mass by transthoracic three-dimensional echocardiography in patients with dilated cardiomyopathy [in German]. Z Kardiol 1999;88:922-31. 44. Kuhl HP, Bucker A, Franke A, et al. Transesophageal 3-dimensional echocardiography: in vivo determination of left ventricular mass in comparison with magnetic resonance imaging. J Am Soc Echocardiogr 2000;13:205-15. 45. Gopal AS, Keller AM, Shen Z, et al. Three-dimensional echocardiography: in vitro and in vivo validation of left ventricular mass and comparison with conventional echocardiographic methods. J Am Coll Cardiol 1994;24:504-13. 46. Gopal AS, Schnellbaecher MD, Shen Z, et al. Clinical use of 3D echocardiography for serial assessment of left ventricular mass regression in hypertensive patients [abstract]. J Am Soc Echocardiogr 1995;8:387. 47. Himelman RB, Cassidy MM, Landzberg JS, Schiller NB. Reproducibility of quantitative two-dimensional echocardiography. Am Heart J 1988;115:425-31. 48. Grandits GA, Liebson PR, Dianzumba S, Prineas RJ. Echocardiography in multicenter clinical trials: experience from the Treatment of Mild Hypertension Study. Control Clin Trials 1994;15:395-410. 49. Palmieri V, Dahlof B, DeQuattro V, et al. Reliability of echocardiographic assessment of left ventricular structure and function: the PRESERVE study: Prospective Randomized Study Evaluating Regression of Ventricular Enlargement. J Am Coll Cardiol 1999;34:1625-32. 50. Himelman RB, Cassidy MM, Landzberg JS, Schiller NB. Reproducibility of quantitative two-dimensional echocardiography. Am Heart J 1988;115:425-31. 51. Gottdiener JS, Livengood SV, Meyer PS, Chase GA. Should echocardiography be performed to assess effects of antihypertensive therapy? Test-retest reliability of echocardiography for measurement of left ventricular mass and function. J Am Coll Cardiol 1995;25:424-30. 52. Mondelli JA, Di Luzio S, Nagaraj A, et al. The validation of volumetric real-time 3-dimensional echocardiography for the determination of left ventricular function. J Am Soc Echocardiogr 2001;14:994-1000. 53. Belohlavek M, Pislaru C, Bae RY, Greenleaf JF, Seward JB. Real-time strain rate echocardiographic imaging: temporal and spatial analysis of postsystolic compression in acutely ischemic myocardium. J Am Soc Echocardiogr 2001;14: 360-9.


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54. Quinones MA, Otto CM, Stoddard M, Waggoner A, Zoghbi WA. Recommendations for quantification of Doppler echocardiography: a report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 2002;15:167-84. 55. Bruch C, Schmermund A, Bartel T, Schaar J, Erbel R. Tissue Doppler imaging: a new technique for assessment of pseudonormalization of the mitral inflow pattern. Echocardiography 2000;17:539-46. 56. Nagueh SF, Middleton KJ, Kopelen HA, Zoghbi WA, Quinones MA. Doppler tissue imaging: a noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol 1997;30:1527-33. 57. Shimizu G, Zile MR, Blaustein AS, Gaasch WH. Left ventricular chamber filling and midwall fiber lengthening in patients with left ventricular hypertrophy: overestimation of fiber velocities by conventional midwall measurements. Circulation 1985;71:266-72. 58. De Simone G, Devereux RB, Roman MJ, et al. Assessment of left ventricular function by the midwall fractional shortening/end-systolic stress relation in human hypertension [published erratum appears in J Am Coll Cardiol 1994;24:844]. J Am Coll Cardiol 1994;23:1444-51. 59. Aurigemma GP, Gottdiener JS, Shemanski L, Gardin JM, Kitzman D. Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: the Cardiovascular Health Study. J Am Coll Cardiol 2001; 37:1042-8. 60. Schmieder RE. Salt intake is related to the process of myocardial hypertrophy in essential hypertension. JAMA 1989; 262:1187-8. 61. Thomson HL, Basmadjian AJ, Rainbird AJ, et al. Contrast echocardiography improves the accuracy and reproducibility of left ventricular remodeling measurements: a prospective, randomly assigned, blinded study. J Am Coll Cardiol 2001; 38:867-75. 62. Chuang ML, Hibberd MG, Salton CJ, et al. Importance of imaging method over imaging modality in noninvasive determination of left ventricular volumes and ejection fraction: assessment by two- and three-dimensional echocardiography and magnetic resonance imaging. J Am Coll Cardiol 2000; 35:477-84. 63. Hundley WG, Kizilbash AM, Afridi I, Franco F, Peshock RM, Grayburn PA. Administration of an intravenous perfluorocarbon contrast agent improves echocardiographic determination of left ventricular volumes and ejection fraction: comparison with cine magnetic resonance imaging. J Am Coll Cardiol 1998;32:1426-32. 64. Grothues F, Smith GC, Moon JC, et al. Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two-dimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy. Am J Cardiol 2002;90:29-34. 65. Foster E, Cahalan MK. The search for intelligent quantitation in echocardiography: “eyeball,” “trackball” and beyond. J Am Coll Cardiol 1993;22:848-50. 66. Cerqueira MD, Weissman NJ, Dilsizian V, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: a statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 2002;105:539-42.

Gottdiener et al 1113

67. Schiller NB, Shah PM, Crawford M, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography: American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 1989;2:358-67. 68. Hillis GS, Moller JE, Pellikka PA, et al. Noninvasive estimation of left ventricular filling pressure by E/e’ is a powerful predictor of survival after acute myocardial infarction. J Am Coll Cardiol 2004;43:360-7. 69. Tsang TS, Barnes ME, Gersh BJ, Bailey KR, Seward JB. Risks for atrial fibrillation and congestive heart failure in patients ⱖ65 years of age with abnormal left ventricular diastolic relaxation. Am J Cardiol 2004;93:54-8. 70. Moller JE, Poulsen SH, Sondergaard E, Seward JB, Appleton CP, Egstrup K. Impact of early changes in left ventricular filling pattern on long-term outcome after acute myocardial infarction. Int J Cardiol 2003;89:207-15. 71. Wang M, Yip GW, Wang AY, et al. Peak early diastolic mitral annulus velocity by tissue Doppler imaging adds independent and incremental prognostic value. J Am Coll Cardiol 2003;41:820-6. 72. Moller JE, Egstrup K, Kober L, Poulsen SH, Nyvad O, Torp-Pedersen C. Prognostic importance of systolic and diastolic function after acute myocardial infarction. Am Heart J 2003;145:147-53. 73. Tsang TS, Gersh BJ, Appleton CP, et al. Left ventricular diastolic dysfunction as a predictor of the first diagnosed nonvalvular atrial fibrillation in 840 elderly men and women. J Am Coll Cardiol 2002;40:1636-44. 74. Whalley GA, Doughty RN, Gamble GD, et al. Pseudonormal mitral filling pattern predicts hospital re-admission in patients with congestive heart failure. J Am Coll Cardiol 2002;39:1787-95. 75. Bella JN, Palmieri V, Roman MJ, et al. Mitral ratio of peak early to late diastolic filling velocity as a predictor of mortality in middle-aged and elderly adults: the Strong Heart Study. Circulation 2002;105:1928-33. 76. Schannwell CM, Schoebel FC, Marx R, Plehn G, Leschke M, Strauer BE. Prognostic relevance of left ventricular diastolic function parameters in dilated cardiomyopathy [in German]. Z Kardiol 2001;90:269-79. 77. Temporelli PL, Corra U, Imparato A, Bosimini E, Scapellato F, Giannuzzi P. Reversible restrictive left ventricular diastolic filling with optimized oral therapy predicts a more favorable prognosis in patients with chronic heart failure. J Am Coll Cardiol 1998;31:1591-7. 78. Cohen GI, Pietrolungo JF, Thomas JD, Klein AL. A practical guide to assessment of ventricular diastolic function using Doppler echocardiography. J Am Coll Cardiol 1996;27: 1753-60. 79. Garcia MJ, Thomas JD, Klein AL. New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1998;32:865-75. 80. Nishimura RA, Tajik AJ. Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician’s Rosetta Stone. J Am Coll Cardiol 1997;30:8-18. 81. Border WL, Michelfelder EC, Glascock BJ, et al. Color M-mode and Doppler tissue evaluation of diastolic function in children: simultaneous correlation with invasive indices. J Am Soc Echocardiogr 2003;16:988-94. 82. Moller JE, Poulsen SH, Sondergaard E, Egstrup K. Preload dependence of color M-mode Doppler flow propagation


1114 Gottdiener et al

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

velocity in controls and in patients with left ventricular dysfunction. J Am Soc Echocardiogr 2000;13:902-9. Garcia MJ, Smedira NG, Greenberg NL, et al. Color Mmode Doppler flow propagation velocity is a preload insensitive index of left ventricular relaxation: animal and human validation. J Am Coll Cardiol 2000;35:201-8. Galderisi M, Benjamin EJ, Evans JC, et al. Intra- and interobserver reproducibility of Doppler-assessed indexes of left ventricular diastolic function in a population-based study (the Framingham Heart Study). Am J Cardiol 1992;70: 1341-6. Appleton CP, Galloway JM, Gonzalez MS, Gaballa M, Basnight MA. Estimation of left ventricular filling pressures using two-dimensional and Doppler echocardiography in adult patients with cardiac disease: additional value of analyzing left atrial size, left atrial ejection fraction and the difference in duration of pulmonary venous and mitral flow velocity at atrial contraction. J Am Coll Cardiol 1993;22: 1972-82. Maeda T, Matsuzaki M, Anno Y, et al. Two-dimensional echocardiographic evaluation of left atrial shape and size [in Japanese]. J Cardiogr 1984;14:311-21. Lester SJ, Ryan EW, Schiller NB, Foster E. Best method in clinical practice and in research studies to determine left atrial size. Am J Cardiol 1999;84:829-32. Kircher B, Abbott JA, Pau S, et al. Left atrial volume determination by biplane two-dimensional echocardiography: validation by cine computed tomography. Am Heart J 1991; 121:864-71. Pritchett AM, Jacobsen SJ, Mahoney DW, Rodeheffer RJ, Bailey KR, Redfield MM. Left atrial volume as an index of left atrial size: a population-based study. J Am Coll Cardiol 2003;41:1036-43. Manolio TA, Gottdiener JS, Tsang TS, Gardin JM. Left atrial dimensions determined by M-mode echocardiography in black and white older(⹖65 years) adults (the Cardiovascular Health Study). Am J Cardiol 2002;90:983-7. Gardin JM, McClelland R, Kitzman D, et al. M-mode echocardiographic predictors of six- to seven-year incidence of coronary heart disease, stroke, congestive heart failure, and mortality in an elderly cohort (the Cardiovascular Health Study). Am J Cardiol 2001;87:1051-7. Rossi A, Tomaino M, Golia G, et al. Usefulness of left atrial size in predicting postoperative symptomatic improvement in patients with aortic stenosis. Am J Cardiol 2000;86:56770. Benjamin EJ, D’Agostino RB, Belanger AJ, Wolf PA, Levy D. Left atrial size and the risk of stroke and death: the Framingham Heart Study. Circulation 1995;92:835-41. Gottdiener JS, Reda DJ, Williams DW, Materson BJ, Cushman W, Anderson RJ. Effect of single-drug therapy on reduction of left atrial size in mild to moderate hypertension: comparison of six antihypertensive agents: the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Circulation 1998;95:2007-14. Triposkiadis F, Tentolouris K, Androulakis A, et al. Left atrial mechanical function in the healthy elderly: new insights from a combined assessment of changes in atrial volume and transmitral flow velocity. J Am Soc Echocardiogr 1995;8: 801-9. Pearlman JD, Triulzi MO, King ME, Abascal VM, Newell J, Weyman AE. Left atrial dimensions in growth and development: normal limits for two-dimensional echocardiography. J Am Coll Cardiol 1990;16:1168-74.

Journal of the American Society of Echocardiography October 2004

97. Schiller NB, Foster E, Redberg RF. Transesophageal echocardiography in the evaluation of mitral regurgitation: the twenty-four signs of severe mitral regurgitation. Cardiol Clin 1993;11:399-408. 98. Cheitlin MD, Armstrong WF, Aurigemma GP, et al. ACC/ AHA/ASE 2003 guideline update for the clinical application of echocardiography: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2003;108:117. 99. Weyman AE. Principles and practice of echocardiography. 2nd ed. Philadelphia: Lea & Febiger; 1994. 100. Otto Catherine. Textbook of clinical echocardiography. 2nd ed. Philadelphia: WB Saunders; 2000. p. 521-46. 101. Feigenbaum H. Echocardiography, 5th ed. Philadelphia: Lea & Febiger; 1994. 102. Recusani F, Bargiggia GS, Yoganathan AP, et al. A new method for quantification of regurgitant flow rate using color Doppler flow imaging of the flow convergence region proximal to a discrete orifice: an in vitro study. Circulation 1991;83:594-604. 103. Rivera JM, Vandervoort PM, Thoreau DH, Levine RA, Weyman AE, Thomas JD. Quantification of mitral regurgitation with the proximal flow convergence method: a clinical study. Am Heart J 1992;124:1289-96. 104. Enriquez-Sarano M, Tajik AJ, Bailey KR, Seward JB. Color flow imaging compared with quantitative Doppler assessment of severity of mitral regurgitation: influence of eccentricity of jet and mechanism of regurgitation. J Am Coll Cardiol 1993;21:1211-9. 105. Xie GY, Berk MR, Hixson CS, Smith AC, De Maria AN, Smith MD. Quantification of mitral regurgitant volume by the color Doppler proximal isovelocity surface area method: a clinical study. J Am Soc Echocardiogr 1995;8:48-54. 106. Grossmann G, Hoffmeister A, Imhof A, Giesler M, Hombach V, Spiess J. Reproducibility of the proximal flow convergence method in mitral and tricuspid regurgitation. Am Heart J 2004;147:721-8. 107. Hagenaars T, Gussenhoven EJ, van Essen JA, Seelen J, Honkoop J, van der LA. Reproducibility of volumetric quantification in intravascular ultrasound images. Ultrasound Med Biol 2000;26:367-74. 108. Mintz GS, Nissen SE, Anderson WD, et al. Standards for the acquisition; measurement; and reporting of intravascular ultrasound studies: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2001;37:1478-92. 109. Panza JA, Quyyumi AA, Brush JE, Epstein SE. Abnormal endothelium-dependent relaxation in patients with essential hypertension. N Engl J Med 1990;323:22-36. 110. Perticone F, Ceravalo R, Pujia A, et al. Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation 2001;104:191-6. 111. Mano T, Masuyama T, Yamamoto K, et al. Endothelial dysfunction in the early stage of atherosclerosis precedes appearance of intimal lesions assessable with intravascular ultrasound. Am Heart J 1996;131:231-8. 112. Reddy KG, Nair RN, Sheehan HM, Hodgson JM. Evidence that selective endothelial dysfunction may occur in the absence of angiographic or ultrasound atherosclerosis in patients with risk factors for atherosclerosis. J Am Coll Cardiol 1994;23:838-43. 113. Nieuw Amerongen GP, Vermeer MA, Negre-Aminou P, Lankelma J, Emeis JJ, van Hinsbergh VW. Simvastatin im-


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114.

115.

116.

117.

118.

119.

120.

121.

122.

123.

124.

125.

126.

127.

proves disturbed endothelial barrier function. Circulation 2000;102:2803-9. Penny WF, Ben Yehuda O, Kuroe K, et al. Improvement of coronary artery endothelial dysfunction with lipid-lowering therapy: heterogeneity of segmental response and correlation with plasma-oxidized low density lipoprotein. J Am Coll Cardiol 2001;37:766-74. Neunteufl T, Kostner K, Katzenschlager R, Zehetgruber M, Maurer G, Weidinger F. Additional benefit of vitamin E supplementation to simvastatin therapy on vasoreactivity of the brachial artery of hypercholesterolemic men. J Am Coll Cardiol 1998;32:711-6. Corretti MC, Anderson TJ, Benjamin EJ, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 2002;39:257-65. Sorensen KE, Celermajer DS, Spiegelhalter DJ, et al. Noninvasive measurement of human endothelium dependent arterial responses: accuracy and reproducibility. Br Heart J 1995;74:247-53. Salonen JT, Salonen R. Ultrasound B-mode imaging in observational studies of atherosclerotic progression. Circulation 1993;87:1156-65. Burke G, Evans G, Riley W, et al. Arterial wall thickness is associated with prevalent cardiovascular disease in middleaged adults: the Atherosclerosis Risk in Communities (ARIC) Study. Stroke 1995;26:386-91. Chambless LE, Heiss G, Folsom AR, et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987-1993. Am J Epidemiol 1997;146:483-94. O’Leary D, Polak J, Kronmal R, Manolio T, Burke G, Wolfson S Jr. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults: Cardiovascular Health Study. N Engl J Med 1999; 340:14-22. Espeland MA, Craven TE, Riley WA, Corson J, Romont A, Furberg CD. Reliability of longitudinal ultrasonographic measurements of carotid intimal-medial thicknesses: Asymptomatic Carotid Artery Progression Study Research Group. Stroke 1996;27:480-5. Tang R, Hennig M, Thomasson B, et al. Baseline reproducibility of B-mode ultrasonic measurement of carotid artery intima-media thickness: the European Lacidipine Study on Atherosclerosis (ELSA). J Hypertens 2000;18:197-201. Howard G, Sharret A, Heiss G, Evans GW, Chambless LE, Riley WA, et al. Carotid artery intimal-media thickness distribution in general populations as evaluated by B-mode ultrasound. Stroke 1993;24:1297-1304. Zanchetti A, Bond MG, Hennig M, et al. Calcium antagonist lacidipine slows down progression of asymptomatic carotid atherosclerosis: principal results of the European Lacidipine Study on Atherosclerosis (ELSA), a randomized, double-blind, long-term trial. Circulation 2002;106:2422-7. Selzer RH, Hodis HN, Kwong-Fu H, et al. Evaluation of computerized edge tracking for quantifying intima-media thickness of the common carotid artery from B-mode ultrasound images. Atherosclerosis 1994;111:1-11. Riley W, Barnes R, Bond M, et al. High-resolution B-mode ultrasound reading methods in the Atherosclerosis Risk in Communities (ARIC) cohort. J Neuroimaging 1991;1:16872.

Gottdiener et al 1115

128. Wendelhag I, Liang Q, Gustavsson T, Wikstrand J. A new automated computerized analyzing system simplifies readings and reduces the variability in ultrasound measurement of intima-media thickness. Stroke 1997;28:2195-200. 129. Gerstenblith G. Frederiksen J, Yin FC, Fortuin N, Lakatta E, Weisfeldt ML. Echocardiographic assessment of a normal adult aging population. Circulation 1977;56:273-8. 130. Gardin JM, Henry WL, Savage DD, Ware JH, Burn C, Borer JS. Echocardiographic measurements in normal subjects: evaluation of an adult population without clinically apparent heart disease. J Clin Ultrasound 1979;7:439-47. 131. Henry WL, Gardin JM, Ware JH. Echocardiographic measurements in normal subjects from infancy to old age. Circulation 2003;62:1054-61. 132. Valdez R, Motta J, London E, et al. Evaluation of the echocardiogram as an epidemiologic tool in an asymptomatic population. Circulation 1979;60:921-9. 133. Savage DD, Abbott RD, Padgett SJ, Anderson SJ, Garrison RJ. Epidemiologic aspects of left ventricular hypertrophy in normotensive and hypertensive subjects. In: ter Keurs HEDJ, ed. Cardiac Left Ventricular Hypertrophy. The Hague: Martinus-Nijhoff; 1983:2-15. 134. Savage DD, Garrison RJ, Kannel WB, Anderson SJ, Feinleib M, Castelli WP. Considerations in the use of echocardiography in epidemiology: the Framingham study. Hypertension 1987;9(Suppl II):II-40-4. 135. Savage DD, Garrison RJ, Kannel WB, et al. The spectrum of left ventricular hypertrophy in a general population sample: the Framingham Study. Circulation 1987;75:I-26-33. 136. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Left ventricular mass and incidence of coronary heart disease in an elderly cohort: the Framingham Heart Study. Ann Intern Med 1989;110:101-7. 137. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990;332:1561-6. 138. Liebson PR. Clinical studies of drug reversal of hypertensive left ventricular hypertrophy. Am J Hypertens 1990;3:512-7. 139. Trimarco B, Wikstrand J. Regression of cardiovascular structural changes by antihypertensive treatment: functional consequences and time course of reversal as judged from clinical studies. Hypertension 1984;6(Suppl 3):III-150. 140. Schulman SP, Weiss JL, Becker LC, et al. The effects of antihypertensive therapy on left ventricular mass in elderly patients. N Engl J Med 1990;322:1350-6. 141. Sen S. Regression of cardiac hypertrophy: experimental animal model. Am J Med 1983;75(Suppl 3A):87. 142. Fouad-Tarazi F, Liebson PR. Echocardiographic studies of regression of left ventricular hypertrophy in hypertension. Hypertension 1987;4(Suppl 2):65-8. 143. Tarazi RC, Sen S, Fouad FM, Wicker P. Regression of myocardial hypertrophy: conditions and sequelae of reversal in hypertensive heart disease. In: Alpert NR, editor. Perspectives in Cardiovascular Research, 7th ed. New York: Raven Press; 1983:637 144. Gottdiener JS, Reda DJ, Massie BM, Materson BJ, Williams DW, Anderson RJ. Effect of single-drug therapy on reduction of left ventricular mass in mild to moderate hypertension: comparison of six antihypertensive agents: the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Circulation 1997;95:2007-14. 145. Papademetriou V, Gottdiener JS, Narayan P, et al. Hydrochlorothiazide is superior to isradipine for reduction of left


Journal of the American Society of Echocardiography October 2004

1116 Gottdiener et al

146.

147.

148.

149.

150.

151.

152.

153.

154.

155.

156.

157.

158.

159.

160.

161.

162.

ventricular mass: results of a multicenter trial: the Isradipine Study Group. J Am Coll Cardiol 1997;30:1802-8. Dahlof B, Devereux R, de Faire U, et al. The Losartan Intervention For Endpoint reduction (LIFE) in Hypertension study: rationale, design, and methods: the LIFE Study Group. Am J Hypertens 1997;10:705-13. Mazur W, Nagueh SF, Lakkis NM, et al. Regression of left ventricular hypertrophy after nonsurgical septal reduction therapy for hypertrophic obstructive cardiomyopathy. Circulation 2001;103:1492-6. De Simone G, Ferrara LA, Di Lorenzo L, Lauria R, Fasano ML. Effects of slow-release nifedipine of left ventricular mass and systolic function in mild or moderate hypertension. Curr Ther Res 1984;36:537-44. Trimarco B, De Luca N, Ricciardelli B, et al. Cardiac function in systemic hypertension before and after reversal of left ventricular hypertrophy. Am J Cardiol 1988;62:745-50. Shahi M, Thom S, Poulter N, Sever PS, Foale RA. Regression of hypertensive left ventricular hypertrophy and left ventricular diastolic function. Lancet 1990;336:458-61. Grandi AM, Venco A, Bertolini A, et al. Left ventricular function after reversal of myocardial hypertrophy in systemic hypertension, and response to acute increase of afterload by cold pressor test. Am J Cardiol 1992;69:1439-41. Galderisi M, Celentano A, Garofalo M, T , et al. Reduction of left ventricular mass by short-term antihypertensive treatment with isradipine: a double-blind comparison with enalapril. Int J Clin Pharmacol Ther 1994;32:312-6. Lacourciere Y, Poirier L, Cleroux J. Physical performance is preserved after regression of left ventricular hypertrophy . J Cardiovasc Pharmacol 1997;30:383-91. Devereux RB, Dahlof B, Levy D, Pfeffer MA. Comparison of enalapril versus nifedipine to decrease left ventricular hypertrophy in systemic hypertension (the PRESERVE trial). Am J Cardiol 1996;78:61-5. Franz IW, Tonnesmann U, Muller JF. Time course of complete normalization of left ventricular hypertrophy during long-term antihypertensive therapy with angiotensin converting enzyme inhibitors. Am J Hypertens 1998;11:631-9. Gottdiener JS. Clinical trials of single-drug therapy for the cardiac effects of hypertension. Am J Hypertens 1999;12: 12S-18. Phillips RA, Ardeljan M, Shimabukuro S, et al. Effects of nifedipine-GITS on left ventricular mass and left ventricular filling. J Cardiovasc Pharmacol 1992;19(Suppl 2):S28-34. Aurigemma GP, Gottdiener JS, Gaasch WH, et al. Ventricular and myocardial function following regression of hypertensive left ventricular hypertrophy. J Am Coll Cardiol 1995; February (special issue):251A. Wachtell K, Bella JN, Rokkedal J, et al. Change in diastolic left ventricular filling after one year of antihypertensive treatment: the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study. Circulation 2002;105:1071-6. Gottdiener JS, Diamond JA, Phillips RA. Hypertension: impact of echocardiographic data on the mechanism of hypertension, treatment options, prognosis and assessment of therapy. In: Otto CM, editor. Clinical Echocardiography, 2nd ed. Philadelphia: WB Saunders; 2000. Heart Failure Society of America (HFSA) practice guidelines. HFSA guidelines for management of patients with heart failure caused by left ventricular systolic dysfunction: pharmacological approaches. J Card Fail 1999;5:357-82. Guidelines for the evaluation and management of heart failure: report of the American College of Cardiology/

163.

164.

165.

166. 167.

168.

169.

170.

171.

172.

173.

174.

175. 176. 177.

178.

179. 180.

American Heart Association Task Force on Practice Guidelines (Committee on Evaluation and Management of Heart Failure). J Am Coll Cardiol 1995;26:1376-98. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293-302. Pennell DJ, Ray SG, Davies G, et al. The Carvedilol Hibernation Reversible Ischaemia Trial, Marker of Success (CHRISTMAS) Study: methodology of a randomised; placebo controlled; multicentre study of carvedilol in hibernation and heart failure. Int J Cardiol 2000;72:265-74. Wong M, Staszewsky L, Volpi A, Latini R, Barlera S, Hoglund C. Quality assessment and quality control of echocardiographic performance in a large multicenter international study: Valsartan in Heart Failure Trial (Val-HeFT). J Am Soc Echocardiogr 2002;15:293-301. Sasayama S. Prognosis of heart failure and factors influencing mortality [in Japanese]. Nippon Rinsho 2003;51:1379-92. Cleland JG, Tendera M, Adamus J, et al, for the PEP Investigators. Perindopril for elderly people with chronic heart failure: the PEP-CHF study. Eur J Heart Fail 1999;1: 211-7. Wong M, Germanson T, Taylor WR, et al. Felodipine improves left ventricular emptying in patients with chronic heart failure: V-HeFT III echocardiographic substudy of multicenter reproducibility and detecting functional change. J Card Fail 2000;6:19-28. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002; 346:1845-53. Capucci A, Romano S, Puglisi A, et al. Dual chamber pacing with optimal AV delay in congestive heart failure: a randomized study. Europace 1999;1:174-8. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002; 346:1845-53. Pitzalis MV, Iacoviello M, Romito R, et al. Cardiac resynchronization therapy tailored by echocardiographic evaluation of ventricular asynchrony. J Am Coll Cardiol 2002;40: 1615-22. Sogaard P, Egeblad H, Kim WY, et al. Tissue Doppler imaging predicts improved systolic performance and reversed left ventricular remodeling during long-term cardiac resynchronization therapy. J Am Coll Cardiol 2002;40:723-30. Bellenger NG, Burgess MI, Ray SG, et al. Comparison of left ventricular ejection fraction and volumes in heart failure by echocardiography, radionuclide ventriculography and cardiovascular magnetic resonance: are they interchangeable? Eur Heart J 2000;21:1387-96. 1999 Heart and Stroke Statistical Update. Dallas Tex: American Heart Association, 1998. Hart RG. Cardiogenic embolism to the brain. Lancet 1992; 339:589-94. Goldman ME, Croft LB, Goldman ME, Croft LB. Echocardiography in search of a cardioembolic source. Curr Probl Cardiol 2002;27:342-8. Klein AL, Grimm RA, Murray RD, et al. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med 2001;344:1411-20. Di Tullio MR, Homma S. Mechanisms of cardioembolic stroke. Curr Cardiol Rep 2002;4:141-8. Klein AL. Emerging role of echocardiography in the evaluation of patients with atrial fibrillation into the new millennium. Echocardiography 2000;17:353-6.


Journal of the American Society of Echocardiography Volume 17 Number 10

181. Thamilarasan M, Klein AL. Transesophageal echocardiography (TEE) in atrial fibrillation. Cardiol Clin 2000;18:819-31. 182. Rodriguez C, Homma S, Di Tullio M. Transesophageal echocardiography in stroke. Cardiol Rev 2000;8:140-7. 183. Homma S, Sacco RL, Di Tullio MR, Sciacca RR, Mohr JP. Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study. Circulation 2002;105:2625-31. 184. Mugge A, Kuhn H, Nikutta P, Grote J, Lopez JA, Daniel WG. Assessment of left atrial appendage function by biplane transesophageal echocardiography in patients with nonrheumatic atrial fibrillation: identification of a subgroup of patients at increased embolic risk. J Am Coll Cardiol 1994;23: 599-607. 185. Goldman ME, Pearce LA, Hart RG, et al. Pathophysiologic correlates of thromboembolism in nonvalvular atrial fibrillation, I: reduced flow velocity in the left atrial appendage (the Stroke Prevention in Atrial Fibrillation [SPAF-III] study). J Am Soc Echocardiogr 1999;12:1080-7. 186. The Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography. Transesophageal echocardiographic correlates of thromboembolism in high-risk patients with nonvalvular atrial fibrillation. Ann Intern Med 1998;128:639-47. 187. Zabalgoitia M, Halperin JL, Pearce LA, Blackshear JL, Asinger RW, Hart RG. Transesophageal echocardiographic correlates of clinical risk of thromboembolism in nonvalvular atrial fibrillation: Stroke Prevention in Atrial Fibrillation III Investigators. J Am Coll Cardiol 1998;31:1622-6. 188. Mohr JP, Thompson JL, Lazar RM, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001;345:1444-51. 189. Leung DY, Grimm RA, Klein AL. Transesophageal echocardiography-guided approach to cardioversion of atrial fibrillation. Prog Cardiovasc Dis 1996;39:21-32. 190. Nakai T, Lesh MD, Gerstenfeld EP, Virmani R, Jones R, Lee RJ. Percutaneous left atrial appendage occlusion (PLAATO) for preventing cardioembolism: first experience in canine model. Circulation 2002;105:2217-22. 191. Kalman JM, Olgin JE, Karch MR, Lesh MD. Use of intracardiac echocardiography in interventional electrophysiology. Pacing Clin Electrophysiol 1997;20:2248-62. 192. Sohn RH, Schiller NB. Left upper pulmonary vein stenosis 2 months after radiofrequency catheter ablation of atrial fibrillation. Circulation 2000;101:e154-5. 193. Khositseth A, Cabalka AK, Sweeney JP, et al. Transcatheter Amplatzer device closure of atrial septal defect and patent foramen ovale in patients with presumed paradoxical embolism. Mayo Clin Proc 2004;79:35-41. 194. Earing MG, Cabalka AK, Seward JB, Bruce CJ, Reeder GS, Hagler DJ. Intracardiac echocardiographic guidance during transcatheter device closure of atrial septal defect and patent foramen ovale. Mayo Clin Proc 2004;79:24-34. 195. US Food and Drug Administration. Heart Valve Guidance, Version 4.1. 1994. 196. Labovitz AJ. Assessment of prosthetic heart valve function by Doppler echocardiography. a decade of experience. Circulation 1989;80:707-9. 197. Tsukamoto M, Inoue S, Ito T, Hachiro Y, Muraki S, Abe T. Functional evaluation of the bileaflet mechanical valve in the aortic position using dobutamine-stress echocardiography: is a 23-mm prosthetic valve adequately large enough? Jpn Circ J 1998;62:817-23.

Gottdiener et al 1117

198. Reisner SA, Meltzer RS. Normal values of prosthetic valve Doppler echocardiographic parameters: a review. J Am Soc Echocardiogr 1998;1:201-10. 199. Olmos L, Salazar G, Barbetseas J, Quiùones MA, Zoghbi WA. Usefulness of transthoracic echocardiography in detecting significant prosthetic mitral valve regurgitation. Am J Cardiol 1999;83:199-205. 200. Chafizadeh ER, Zoghbi WA. Doppler echocardiographic assessment of the St. Jude Medical prosthetic valve in the aortic position using the continuity equation. Circulation 2003;83:213-23. 201. Baumgartner H, Kratzer H, Helmreich G, Kuehn P. Determination of aortic valve area by Doppler echocardiography using the continuity equation: a critical evaluation. Cardiology 1990;77:101-11. 202. Flachskampf FA, O’Shea JP, Griffin BP, Guerrero L, Weyman AE, Thomas JD. Patterns of normal transvalvular regurgitation in mechanical valve prostheses. J Am Coll Cardiol 1991;18:1493-8. 203. Burstow DJ, Nishimura RA, Bailey KR, et al. Continuous wave Doppler echocardiographic measurement of prosthetic valve gradients: a simultaneous Doppler-catheter correlative study. Circulation 1989;80:504-14. 204. Baumgartner H, Khan S, DeRobertis M, Czer L, Maurer G. Discrepancies between Doppler and catheter gradients in aortic prosthetic valves in vitro: a manifestation of localized gradients and pressure recovery. Circulation 1990;82:1467-75. 205. Yun KLAU, Sintek CF, Fletcher AD, et al. Aortic valve replacement with the freestyle stentless bioprosthesis: fiveyear experience. Circulation 1999;100:17-23. 206. Baumgartner H, Khan S, DeRobertis M, Czer L, Maurer G. Effect of prosthetic aortic valve design on the Dopplercatheter gradient correlation: an in vitro study of normal St. Jude, Medtronic-Hall, Starr-Edwards and Hancock valves. J Am Coll Cardiol 1992;19:324-32. 207. Mohr-Kahaly S, Kupferwasser I, Erbel R, Oelert H, Meyer J. Regurgitant flow in apparently normal valve prostheses: improved detection and semiquantitative analysis by transesophageal two-dimensional color-coded Doppler echocardiography. J Am Soc Echocardiogr 1990;3:187-95. 208. Dumesnil JG, Honos GN, Lemieux M, Beauchemin J. Validation and applications of mitral prosthetic valvular areas calculated by Doppler echocardiography. Am J Cardiol 1990;65:1443-8. 209. Bitar JN, Lechin ME, Salazar G, Zoghbi WA. Doppler echocardiographic assessment with the continuity equation of St. Jude Medical mechanical prostheses in the mitral valve position. Am J Cardiol 2003;76:287-93. 210. Daniel LB, Grigg LE, Weisel RD, Rakowski H. Comparison of transthoracic and transesophageal assessment of prosthetic valve dysfunction. Echocardiography 1990;7:83-95. 211. Khandheria BK, Seward JB, Oh JK, et al. Value and limitations of transesophageal echocardiography in assessment of mitral valve prostheses. Circulation 1991;83:1956-68. 212. Hole T, Otterstad JE, St John SM, Froland G, Holme I, Skjaerpe T. Differences between echocardiographic measurements of left ventricular dimensions and function by local investigators and a core laboratory in a 2-year follow-up study of patients with an acute myocardial infarction. Eur J Echocardiogr 2002;3:263-70. 213. Oh JK. Is core laboratory essential for using echocardiography in clinical trials? Controlled vs random error. Eur J Echocardiogr 2002;3:245-7.


Journal of the American Society of Echocardiography October 2004

1118 Gottdiener et al

214. Ehler D, Carney DK, Dempsey AL, et al. Guidelines for cardiac sonographer education: recommendations of the American Society of Echocardiography Sonographer Training and Education Committee. J Am Soc Echocardiogr 2001;14:77-84. 215. Hodis H, Mack W, LaBree L, et al. The role of carotid arterial intima-medial thickness in predicting clinical coronary events. Ann Intern Med 1998;128:262-9. 216. Taylor AJ, Kent SM, Flaherty PJ, Coyle LC, Markwood TT, Vernalis MN. ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness. Circulation 2002;106:2055-60. 217. Sawayama Y, Shimizu C, Maeda N, et al. Effects of probucol and pravastatin on common carotid atherosclerosis in patients with asymptomatic hypercholesterolemia: Fukuoka Atherosclerosis Trial (FAST). J Am Coll Cardiol 2002;39: 610-6. 218. Byington RP, Furberg CD, Crouse JR III, Espeland MA, Bond MG. Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries (PLAC-II). Am J Cardiol 1995;76:54C59C. 219. Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective; randomised; double-blind trial. Lancet 2001;357:577-81. 220. MacMahon S, Sharpe N, Gamble G, et al. Effects of lowering average of below-average cholesterol levels on the progression of carotid atherosclerosis: results of the LIPID Atherosclerosis Substudy: LIPID Trial Research Group. Circulation 1998;97:1784-90. 221. Hedblad B, Wikstrand J, Janzon L, Wedel H, Berglund G. Low-dose metoprolol CR/XL and fluvastatin slow progression of carotid intima-media thickness: main results from the Beta-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS). Circulation 2001;103:1721-6. 222. Salonen R, Nyyssonen K, Porkkala E, et al. Kuopio Atherosclerosis Prevention Study (KAPS): a population-based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries. Hypertension 2003;92:1758-64. 223. de Groot E, Jukema JW, Montauban van Swijndregt AD, et al. B-mode ultrasound assessment of pravastatin treatment effect on carotid and femoral artery walls and its correlations with coronary arteriographic findings: a report of the Regression Growth Evaluation Statin Study (REGRESS). J Am Coll Cardiol 1998;31:1561-7. 224. Mercuri M, Bond MG, Sirtori CR, et al. Pravastatin reduces carotid intima-media thickness progression in an asymptomatic hypercholesterolemic Mediterranean population: the Carotid Atherosclerosis Italian Ultrasound Study. Am J Med 1996;101:627-34. 225. Hodis HN, Mack WJ, LaBree L, et al. Reduction in carotid arterial wall thickness using lovastatin and dietary therapy: a randomized controlled clinical trial. Ann Intern Med 1996; 124:548-56. 226. Pitt B, Byington RP, Furberg CD, et al. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events: PREVENT Investigators. Circulation 2000; 102:1503-10. 227. Borhani NO, Mercuri M, Borhani PA, et al. Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis

228.

229.

230.

231.

232.

233.

234.

235.

236.

237.

238.

239.

240.

241.

242.

Study (MIDAS): a randomized controlled trial. JAMA 2003;276:785-91. Zanchetti A, Rosei EA, Dal Palu C, Leonetti G, Magnani B, Pessina A. The Verapamil in Hypertension and Atherosclerosis Study (VHAS): results of long-term randomized treatment with either verapamil or chlorthalidone on carotid intima-media thickness. J Hypertens 1998;16:1667-76. Simon A, Gariepy J, Chironi G, Megnien JL, Levenson J. Intima-media thickness: a new tool for diagnosis and treatment of cardiovascular risk. J Hypertens 2002;20:159-69. Lonn E, Yusuf S, Dzavik V, et al. Effects of ramipril and vitamin E on atherosclerosis: the Study to Evaluate Carotid Ultrasound Changes in Patients Treated With Ramipril and Vitamin E (SECURE). Circulation 2001;103:919-25. Savage DD, Garrison AR, Kannel WB. The spectrum of left ventricular hypertrophy in a general population sample: the Framingham Study. Circulation 1987;75:I26-33. Hammond IW, Devereux RB, Aldermann MA. The prevalence and correlates of echocardiographic left ventricular hypertrophy among employed patients with uncomplicated hypertension. J Am Coll Cardiol 1986;7:639-50. Senni M, Tribouilloy CM, Rodeheffer RJ, et al. Congestive heart failure in the community: a study of all incident cases in Olmsted County, Minnesota, in 1991. Circulation 1998;98: 2282-9. Gardin JM, Wong ND, Bommer W, et al. Echocardiographic design of a multi-center investigation of free-living elderly subjects: the Cardiovascular Health Study. J Am Soc Echocardiogr 1992;5:63-72. Gardin JM, Wagenknecht LE, Anton-Culver H, et al. Relationship of cardiovascular risk factors to echocardiographic left ventricular mass in healthy young black and white adult men and women: the CARDIA study: Coronary Artery Risk Development in Young Adults. Circulation 1995;92:380-7. Lindroos M, Kupari M, Heikkila J, Tilvis R. Echocardiographic evidence of left ventricular hypertrophy in a general aged population. Am J Cardiol 1994;74:385-90. Ilercil A, O’Grady MJ, Roman MJ, et al. Reference values for echocardiographic measurements in urban and rural populations of differing ethnicity: the Strong Heart Study. J Am Soc Echocardiogr 2001;14:601-11. De Simone G, Palmieri V, Bella JN, et al. Association of left ventricular hypertrophy with metabolic risk factors: the HyperGEN study. J Hypertens 2002;20:323-31. Devereux RB, Roman MJ, Paranicas M, et al. A populationbased assessment of left ventricular systolic dysfunction in middle-aged and older adults: the Strong Heart Study. Am Heart J 2001;141:439-46. Liebson PR, Grandits GA, Dianzumba S, et al. Comparison of five antihypertensive monotherapies and placebo for change in left ventricular mass in patients receiving nutritional-hygienic therapy in the Treatment of Mild Hypertension Study (TOMHS). Circulation 1995;91:698-706. Devereux RB, Palmieri V, Liu JE, et al. Progressive hypertrophy regression with sustained pressure reduction in hypertension: the Losartan Intervention For Endpoint Reduction study. J Hypertens 2002;20:1445-50. Devereux RB, Palmieri V, Sharpe N, et al. Effects of oncedaily angiotensin-converting enzyme inhibition and calcium channel blockade-based antihypertensive treatment regimens on left ventricular hypertrophy and diastolic filling in hypertension: the Prospective Randomized Enalapril Study


Journal of the American Society of Echocardiography Volume 17 Number 10

243.

244.

245.

246.

247.

248.

Evaluating Regression of Ventricular Enlargement (PRESERVE) trial. Circulation 2001;104:1248-54. St. John Sutton M, Pfeffer MA, Plappert T, et al. Quantitative two-dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction: the protective effects of captopril. Circulation 1994;89:68-75. Wong M, Johnson G, Shabetai R, et al. Echocardiographic variables as prognostic indicators and therapeutic monitors in chronic congestive heart failure: Veterans Affairs cooperative studies V-HeFT I and II: V-HeFT VA Cooperative Studies Group. Circulation 1993;87:V165-70. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9-13. Hall SA, Cigarroa CG, Marcoux L, Risser RC, Grayburn PA, Eichhorn EJ. Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with beta-adrenergic blockade. J Am Coll Cardiol. 1995;25:1154-61. Doughty RN, Whalley GA, Gamble G, MacMahon S, Sharpe N, for the Australia-New Zealand Heart Failure Research Collaborative Group. Left ventricular remodeling with carvedilol in patients with congestive heart failure due to ischemic heart disease. J Am Coll Cardiol 1997;29:1060-6. Tang WHW, Khot UN, Larson MS, et al. Baseline clinical parameters do not predict left ventricular ejection im-

Gottdiener et al 1119

249.

250.

251.

252.

253.

254.

255.

provement following carvedilol therapy in heart failure. J Am Coll Cardiol 2000;35:207A. Arcensio SR, Barretto AC, Szambock F, et al. Comparative study between ibopamine and captopril in mild and moderate heart failure: a double-blind study [in Portugese]. Arq Bras Cardiol. 1994;63:409-13. Jette M, Heller R, Landry F, Blumchen G. Randomized 4-week exercise program in patients with impaired left ventricular function. Circulation 1991;84:1561-7. Pu CT, Johnson MT, Forman DE, et al. Randomized trial of progressive resistance training to counteract the myopathy of chronic heart failure. J Appl Physiol 2003;90:2341-50. Cabell CH, Velazquez EJ, Dumesnil JG, et al. Echocardiographic predictors of mortality in nonischemic cardiomyopathy: report from the PRAISE-2 Echocardiographic Substudy. Am Coll Cardiol 2002;37:648A. Swedberg K, Pfeffer M, Granger C, et al. Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity (CHARM): rationale and design: Charm-Programme Investigators. J Card Fail 1999;5:276-82. Murray RD, Shah A, Jasper SE, et al. Transesophageal echocardiography guided enoxaparin antithrombotic strategy for cardioversion of atrial fibrillation: the ACUTE II pilot study. Am Heart J 2000;139:1-7. Pullicino PM, Halperin JL, Thompson JL. Stroke in patients with heart failure and reduced left ventricular ejection fraction. Neurology 2000;54:288-94.

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Writing Committee: John S. Gottdiener, MD (Chair), James Bednarz, BS, RDCS, Richard Devereux, MD, Julius Gardin, MD, Allan Klein, MD, Warren...

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